INTERLEUKIN 8 (IL8)
Interleukin-8 | IL8
J Biol Regul Homeost Agents. 2019 Apr 4;33(2). [Epub ahead of print]
Effects of euphorbia kansui on the serum levels of IL-6, TNF-α, NF-κB, sTNFR and IL-8 in patients with severe acute pancreatitis.
In this study, effects of euphorbia kansui on serum levels of inflammatory factors in patients with severe acute pancreatitis were investigated, and the mechanisms underlying the role of Euphorbia kansui in the treatment of severe acute pancreatitis were discussed. 36 patients hospitalized in the Third Affiliated Hospital of Wenzhou Medical University from March 2017 to May 2018 due to severe acute pancreatitis were selected and divided into two groups using a randomized grouping method. ELISA (enzyme-linked immunosorbent assay) was used to detect expressions of various inflammatory cytokines, such as tumor necrosis factor α (TNF-α), soluble TNF receptors (sTNFR), nuclear factor-κB (NF-κB), interleukin-6 (IL-6), and interleukin-8 (IL-8), in the serum of patients at different time points. The results showed no significant difference between the two groups in terms of age, gender, predisposing factors, Balthaza CT scores, and APACHEII (Acute Physiology and Chronic Health Evaluation) scores.
According to the experimental results, euphorbia kansui effectively reduced the expression of inflammation related cytokines, such as NF-κB, TNF-α, sTNFR, IL-6, and IL-8, in the serum of patients with severe acute pancreatitis. It was also proposed that euphorbia kansui hindered the release of inflammatory factors and treated SAP by inhibiting the activation of the NF-κB signaling pathway.
Cell Death Dis. 2019 Mar 29;10(4):292. doi: 10.1038/s41419-019-1387-6.
Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma.
Emerging evidence reveals enrichment of glioma-initiating cells (GICs) following therapeutic intervention. One factor known to contribute to this enrichment is cellular plasticity-the ability of glioma cells to attain multiple phenotypes. To elucidate the molecular mechanisms governing therapy-induced cellular plasticity, we performed genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq) and gene expression analysis (gene microarray analysis) during treatment with standard of care temozolomide (TMZ) chemotherapy. Analysis revealed significant enhancement of open-chromatin marks in known astrocytic enhancers for interleukin-8 (IL-8) loci as well as elevated expression during anti-glioma chemotherapy.
The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project data demonstrated that IL-8 transcript expression is negatively correlated with GBM patient survival (p = 0.001) and positively correlated with that of genes associated with the GIC phenotypes, such as KLF4, c-Myc, and HIF2α (p < 0.001). Immunohistochemical analysis of patient samples demonstrated elevated IL-8 expression in about 60% of recurrent GBM tumors relative to matched primary tumors and this expression also positively correlates with time to recurrence.
Exposure to IL-8 significantly enhanced the self-renewing capacity of PDX GBM (average threefold, p < 0.0005), as well as increasing the expression of GIC markers in the CXCR2 population. Furthermore, IL-8 knockdown significantly delayed PDX GBM tumor growth in vivo (p < 0.0005). Finally, guided by in silico analysis of TCGA data, we examined the effect of therapy-induced IL-8 expression on the epigenomic landscape of GBM cells and observed increased trimethylation of H3K9 and H3K27.
Our results show that autocrine IL-8 alters cellular plasticity and mediates alterations in histone status. These findings suggest that IL-8 signaling participates in regulating GBM adaptation to therapeutic stress and therefore represents a promising target for combination with conventional chemotherapy in order to limit GBM recurrence.
Cancer Cell Int. 2019 Mar 20;19:64. doi: 10.1186/s12935-019-0772-7. eCollection 2019.
Pepsin promotes IL-8 signaling-induced epithelial-mesenchymal transition in laryngeal carcinoma.
Laryngopharyngeal reflux (LPR), with its increasing morbidity, is attracting considerable attention. In recent years, the causal role between LPR and laryngeal carcinoma has been debated. The main harmful component of LPR is pepsin, which has been shown to induce mucosal inflammation by damaging the mucous membrane. Thus, pepsin is linked to an increased risk of laryngeal carcinoma, although the potential mechanism remains largely unknown.
The human laryngeal carcinoma cell lines Hep-2 and Tu212 were exposed to different pepsin concentrations and the morphology, proliferation, migration, secretion of inflammatory cytokines, and epithelial-mesenchymal transition (EMT) of the cells were assessed. To evaluate whether interleukin-8 (IL-8) had a causal relationship with pepsin and EMT, an IL-8 inhibitor was used to suppress IL-8 secretion during pepsin exposure and the expression of EMT markers, cell proliferation, and migration were analyzed.
Pepsin promoted proliferation, colony formation, migration, and IL-8 secretion of Hep-2 and Tu212 cells in vitro. Furthermore, increased pepsin concentrations changed the morphology of Hep-2 and Tu212 cells; levels of the epithelial marker E-cadherin were reduced and those of mesenchymal markers vimentin and β-catenin and the transcription factors snail and slug were elevated. A similar effect was observed in laryngeal carcinoma tissues using immunohistochemistry. IL-8 level was reduced and EMT was restored when pepsin was inhibited by pepstatin. EMT was weakened after exposure to the IL-8 inhibitor, with significant reduction in pepsin-induced cell proliferation and migration.
Pepsin may induce EMT in laryngeal carcinoma through the IL-8 signaling pathway, which indicates that it has potential role in enhancing cell proliferation and metastasis of laryngeal carcinoma.
Reproduction. 2019 Apr 1. pii: REP-18-0618.R1. doi: 10.1530/REP-18-0618. [Epub ahead of print]
Interleukin in endometriosis-associated infertility-pelvic pain: systematic review and meta-analysis.
The objective is to study the significance of altered interleukin levels in endometriosis-related infertility or pelvic pain. The present systematic review and meta-analysis includes a discussion on interleukin roles in the physiopathology of endometriosis-associated infertility and/or pelvic pain. We included all studies in which interleukins in peritoneal fluid, follicular fluid or serum from patients were measured and that correlated the findings with either peritoneal or deep endometriosis-associated infertility or pelvic pain. For the meta-analysis, we selected studies on the following cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8).
Endometriosis is a chronic inflammatory disease. Inflammatory processes clearly participate in the etiology of endometriosis. Cytokines are mediators of inflammation and increase in their concentration in plasma or other body fluids signal the presence and extent of tissue lesions. A number of studies have reported on the association between higher cytokine levels and progression or maintenance of endometriosis and coexisting infertility or pelvic pain. The results of the analyses support that an association exists between elevated serum IL-6 and/or IL-8 concentrations, and the occurrence of endometriosis-associated infertility. Such association was not found for endometriosis-associated pain. In spite of accumulated evidence on the association of pro-inflammatory cytokines and endometriosis it still is not clear, if and how these mediators participate in the physiopathology of endometriosis-associated infertility or pelvic pain, in part due to poor quality of the evidence established in the vast majority of interleukins and challenges in endometriosis research reproducibility.
Brain Behav Immun. 2019 Apr 3. pii: S0889-1591(18)31167-X. doi: 10.1016/j.bbi.2019.04.004. [Epub ahead of print]
Family-Based Analyses Reveal Novel Genetic Overlap Between Interleukin-8 and Risk for Suicide Attempt.
Suicide is major public health concern. It is imperative to find robust biomarkers so that at-risk individuals can be identified in a timely and reliable manner. Previous work suggests mechanistic links between increased inflammation and risk for suicide, but questions remain regarding the etiology of this association, as well as the roles of sex and BMI. Analyses were conducted using a randomly-ascertained extended-pedigree sample of 1884 Mexican-American individuals (60% female, mean age=42.04, range=18-97). Genetic correlations were calculated between IL-6 and IL-8, and lifetime risk for suicide attempt. The potentially confounding effects of sex and BMI were considered. 159 individuals endorse a lifetime suicide attempt.
IL-8 and IL-6 shared significant genetic overlap with risk for suicide attempt shared significant genetic overlap (ρg=0.49, pFDR=7.67x10-03; ρg=0.53, pFDR=0.01), but for IL-6 this was attenuated when BMI was included as a covariate (ρg=0.37, se=0.23, pFDR=0.12). Suicide attempts were significantly more common in females (pFDR=0.01) and the genetic overlap between IL-8 and risk for suicide attempt was significant in females (ρg=0.56, pFDR=0.01), but not in males (ρg=0.44, pFDR=0.30).
These results demonstrate that: IL-8 shares genetic influences with risk for suicide attempt; females drove this effect; and BMI should be considered when assessing the association between IL-6 and suicide. This finding represents a significant advancement in knowledge by demonstrating that inflammation alterations are not simply a secondary manifestation of suicidal behavior, but rather, the pathophysiology of suicide attempts is, at least partly, underpinned by the same biological mechanisms responsible for regulating inflammatory response.
J Am Coll Cardiol. 2018 Jul 10;72(2):187-198. doi: 10.1016/j.jacc.2018.04.053.
Association of IL-8 With Infarct Size and Clinical Outcomes in Patients With STEMI.
Little is known about the role of interleukin (IL)-8 in patients with acute ST-segment elevation myocardial infarction (STEMI).
The aims of this study were to evaluate, in STEMI patients, the temporal profile of IL-8 and possible associations with left ventricular (LV) function and remodeling, infarct size, microvascular obstruction, myocardial salvage, and future clinical events.
A total of 258 patients with STEMI were included. Blood samples were drawn before and immediately after percutaneous coronary intervention (PCI), at day 1, and after 4 months. Cardiac magnetic resonance imaging was performed in the acute phase and after 4 months. Clinical events were registered during 12 months' follow-up and all-cause mortality after median 70 months' follow-up.
Patients with IL-8 levels greater than the median measured both immediately after PCI and at day 1 had larger final infarct size, lower LV ejection fraction, larger increase in LV end-diastolic volume, and higher frequency of microvascular obstruction. After multivariate adjustment, high IL-8 levels at day 1 were associated with an increased risk of developing a large MI and having reduced LV ejection fraction at 4 months, also after adjustment for peak troponin value. Patients with IL-8 levels in the highest quartile measured at all sampling points were more likely to have a clinical event during the first 12 months after the MI and had lower overall survival during long-term follow-up.
High levels of circulating IL-8 were associated with large infarct size, impaired recovery of LV function, and adverse clinical outcome in patients with STEMI, suggesting IL-8 as a future therapeutic target based on its important role in post-infarction inflammation.
Arterioscler Thromb Vasc Biol. 2017 Oct;37(10):1819-1827. doi: 10.1161/ATVBAHA.117.309794. Epub 2017 Aug 3.
Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis.
Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases.
APPROACH AND RESULTS:
We performed next-generation RNA sequencing on monocytes extracted from whole blood clots and using a purified plasma clot system. Numerous mRNAs were differentially expressed by monocytes embedded in clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 (monocyte chemoattractant protein-1) were among the upregulated transcripts in both models. Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in lipopolysaccharide-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (ie, 1-2 hours) reduced the synthesis of IL-8 and MCP-1, whereas delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1.
These findings demonstrate that clots are potent inducers of monocyte gene expression and that timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and MCP-1. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically proven efficacy of fibrinolytic drug treatment within hours of stroke onset.
Tanaffos. 2018 Jan;17(1):13-21.
The Significance of Serum Interleukin-8 in Acute Exacerbations of Chronic Obstructive Pulmonary Disease.
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is closely related to disease mortality. Systemic inflammation is considered to be involved in the pathogenesis of AECOPD. The current study aimed to investigate the clinical significance of the classic chemokine interleukin (IL)-8 in serum during AECOPD.
MATERIALS AND METHODS:
In this current cross sectional, observational study, 50 patients with AECOPD, 25 patients with stable COPD and 25 healthy nonsmokers as the control group were selected. Clinical characteristics and spirometry data were collected. All patients were classified as grade 1-4 based on forced expiratory volume in 1 second (FEV1) after bronchodilation according to the GOLD severity classification and were divided into frequent exacerbation (FE) group (≥2 times/year) and non-frequent exacerbation (NFE) group (<1 time/year) according to acute exacerbation (AE) times in the previous 12 months before the visit. The serum IL-8, IL-6, tumor necrosis factor (TNF)-α, and superoxide dismutase levels were measured by the enzyme-linked immunosorbent assay technique.
Serum IL-8 levels increased sequentially from controls [9.45 pg/mL (ranged: 6.85-38.4)], to stable [51.60 pg/mL (ranged: 22.4-131.1)], and exacerbation stage [129 pg/mL (ranged: 57.7-374)]. The level of serum IL-8 was significant higher in patients with FE than that of patients with NFE (209.0 pg/mL (ranged: 115-472) vs 65.6 pg/mL (ranged: 11.2-149.3), P=0.008). A receiver operating characteristics curve (ROC) generated to evaluate IL-8, IL-6, and TNF-α levels to discriminate between patients with and without exacerbation showed that the total area under the curve (AUC) was 0.71 (95% confidence interval (CI): 0.5764-0.8381; P=0.003), 0.54 (95%CI: 0.4048-0.6943; P=0.54), and 0.52 (95%CI: 0.3912-0.6656; P= 0.7).
Serum IL-8 is a sensitive, easy-to-measure, and inexpensive biomarker to give an indication of the course of COPD during exacerbation, and is a target to be explored further as a predictor to distinguish the patients prone to exacerbation.
Plasma interleukin-8 levels are persistently elevated for 1 month after minimally invasive colorectal resection for colorectal cancer.
Mol Clin Oncol 2018 Mar 18;8(3):471-476. Epub 2017 Dec 18.
Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York, NY 10019, USA.
Minimally invasive colorectal resection (MICR) for colorectal cancer (CRC) is associated with elevated levels of seven proangiogenic proteins that persist for 2-4 weeks after surgery. The proangiogenic plasma may promote tumor growth (circulating tumor cells CTCs) postoperatively in patients with residual cancer.
To the best of our knowledge, the impact of surgery on interleukin 8 (IL-8) levels is unknown. The aim of the present study was to evaluate plasma IL-8 levels after MICR for CRC. Patients with CRC enrolled in an institutional review board-approved plasma/data bank who underwent MICR were eligible.
Blood samples were taken preoperatively (preop) and at multiple postoperative (postop) time points, and were stored at -80°C. Only patients for whom preop, postop day (POD) 1, POD 3 and at least 1 late postop plasma samples (POD7-34) available were enrolled. Clinical, demographical and pathological data were collected. IL-8 levels were determined via ELISA and results were reported as the mean and ± standard deviation. The Wilcoxon signed rank test was used for analysis with P<0.05 used as the significance threshold.
A total of 73 CRC patients (colon, 62%; rectal, 38%) who underwent MICR (laparoscopic-assisted, 60%; hand-assisted, 40%) were studied. The mean preop IL-8 level was 20.4±10.6 pg/ml.
Significant elevations in plasma IL-8 levels were noted compared with preop levels on POD1 (43.1±38.6; n=72; P<0.0001), POD 3 (33.0±30.1; n=71; P<0.0001), POD7-13 (29.9±21.9; n=50; P<0.0001), POD14-20 (33.1±18.3; n=24; P=0.002), and for the POD21-27 time point (24.0±9.2; n=16; P=0.002).
In conclusion, plasma IL-8 levels were significantly elevated from baseline for 4 weeks after MICR for CRC. In conjunction with the other proangiogenic MICR-associated blood compositional changes, increased IL-8 levels may promote tumor angiogenesis and growth postop.
[Factors associated with levels of interleukins -18, -8, and -6 in hypertensive patients at high and very high cardiovascular risk].
Kardiologiia 2017 SMar;57(S3):69-75
Federal State Budgetary Educational Institution of Higher Education, "Pirogov Russian National Research Medical University" of the Ministry of Health of the Russian Federation.
Aim: To identify the most significant factor influencing blood levels of cytokines in patients at high and very high cardiovascular risk.
Materials And Methods: A patient base from the "Management of chronic patients with multiple diseases" project was analyzed. 523 patients (mean age, 87±17.8) were included.
Plasma samples were analyzed for concentrations of sodium, creatinine, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, and NT-proBNP. GFR was calculated using the CKD-EPI formula. Time-related CHF progression was assessed in one year; the time-related progression was considered an increase in CHF stage. Salt consumption was determined using the Charlton: SaltScreener questionnaire at the baseline visit and at one year. Low-salt diet containing 5 g of salt per day was recommended to all patients; 3.5 g of salt per day was recommended to patients with a documented diagnosis of CHF. Statistical analysis was performed using the Statistica 10.0 software.
Results: 52.2 % of included patients consumed 6-10 g of salt per day; 43.4 % of patients consumed 10 g of salt or more per day; and only 4.4 % of patients consumed 5 g of salt or less per day. 21 % of included patients were at high risk of cardiovascular complications whereas for the vast majority of patients (79 %), the risk was stratified as very high. Two clusters of patients were formed based on the grade of hypertension, one-year CHF progression, and plasma levels of IL-6, -8, and -18. The one-year progression of CHF most significantly influenced the levels of IL-18, -8, and -6. The IL-6 level was correlated with the NT-proBNP level; an approximately similar degree of correlation was found for NT-proBNP and BP.
Conclusion: Therefore, the performed statistical analysis determined correlations between the following factors: IL-6 level, NTproBNP level, and one-year CHF progression.
Interleukin 8 activity influences the efficacy of adenoviral oncolytic immunotherapy in cancer patients.
Oncotarget 2018 Jan 5;9(5):6320-6335. Epub 2018 Jan 5.
Cancer Gene Therapy Group, University of Helsinki, Faculty of Medicine, Helsinki, Finland.
After the landmark approval of T-VEC, oncolytic viruses are finding their way to the clinics. However, response rates have still room for improvement, and unfortunately there are currently no available markers to predict responses for oncolytic immunotherapy. Interleukin 8 (IL-8) production is upregulated in many cancers and it also connects to several pathways that have been shown to impair the efficacy of adenoviral immunotherapy.
We studied the role of IL-8 in 103 cancer patients treated with oncolytic adenoviruses. We found high baseline serum IL-8 concentration to be independently associated with poor prognosis (p<0.001).
Further, normal baseline IL-8 was associated with improved prognostic potential of calculation of the neutrophil-to-lymphocyte ratio (p<0.001). Interestingly, a decrease in IL-8 concentration after treatment with oncolytic adenovirus predicted better overall survival (p<0.001) and higher response rate, although this difference was not significant (p=0.066).
We studied the combination of adenovirus and IL-8 neutralizing antibodyin single cell suspensions and in co-cultures of tumor-associated CD15+ neutrophils and CD3+ tumor-infiltrating lymphocytes derived from fresh patient tumor samples. These results indicate a role for IL-8 as a biomarker in oncolytic virotherapy, but additionally provide a rationale for targeting IL-8 to improve treatment efficacy.
In conclusion, curtailing the activity of IL-8 systemically or locally in the tumor microenvironment could improve anti-tumor immune responses resulting in enhanced efficacy of adenoviral immunotherapy of cancer.
Neuroinflammation is a critical component in the pathogenesis of neurodegenerative diseases. Evidence suggests that activated microglia serve as a primary source for a host of inflammatory mediators which in assemblage can lead to neurotoxicity in inflamed brain. Mobilization of chemokine factors is a response to changes in brain homeostatic conditions leading to localized accumulation of reactive microglia at target sites.
In particular, levels of the chemokine IL -8 are significantly elevated in neurodegenerative disease. The putative roles of IL-8-mediated chemotactic responses in neuroinflammation have been most extensively examined in AD brain. Evidence from in vitro studies relevant to AD, use of AD animal models and analysis of IL-8 levels in human brain suggest that resident brain microglia are the primary cell both responding to, and producing, the chemokine. Thus autocrine responses to brain insults from activated microglia include increased levels of IL -8 which contribute to a positive feedback process amplifying and sustaining inflammatory reactivity in AD brain.
Localized and chronic microglial activation in response to Aβ deposits is associated with sustained cellular production of a milieu of inflammatory mediators including pro-inflammatory cytokines, reactive oxygen species and matrix metalloproteinases which in assemblage can cause abnormalities to blood vessels and neurotoxicity. Pharmacological modulation of IL-8 signaling pathways, including inhibition of CXCR2 receptor in microglia, is suggested as a clinical strategy to reduce chemotactic-dependent inflammation and provide neuroprotection in neurodegenerative disease.
Interleukin-8 (IL-8) is produced by phagocytes and mesenchymal cells exposed to inflammatory stimuli (e.g., interleukin-1 or tumor necrosis factor) and activates neutrophils inducing, chemotaxis, exocytosis and the respiratory burst. In vivo, IL-8 elicits a massive neutrophil accumulation at the site of injection. Five neutrophil-activating cytokines similar to IL-8 in structure and function have been identified recently.
IL-8 and the related cytokines are produced in several tissues upon infection, inflammation, ischemia, trauma etc., and are thought to be the main cause of local neutrophil accumulation.
IL-8 is believed to play a role in the pathogenesis of bronchiolitis, a common respiratory tract disease caused by viral infection.
Interleukin-8 plays an important role in chemotaxis and functioning of leukocytes and is locally produced in infected tissues; it is seen in abundance in the urine of individuals with Urinary Tract Infection.
Inflammatory basis of atherosclerosis, several pro- or anti-inflammatory agents have been examined as potential mediators of the biochemical pathways of lesion formation.
Interleukin (IL)-8 was first characterized in 1987. Since then, knowledge regarding its role in leucocyte trafficking and activation has advanced rapidly, especially in the field of cardiovascular disease.
In the scientific literature, there is sufficient evidence to support beyond any doubt the involvement of IL-8 in the establishment and preservation of the inflammatory micro-environment of the insulted vascular wall.
Elevated IL8 is associated with chronic systemic inflammation including: ‘Progressive vascular disease, atherosclerosis lesions, main source for atherosclerosis plagues, predictive biomarker for ischemia induced oxidative stress (page355 1st column last para 1.3), directly involved in pathogenesis of hypertension (p355 2nd column last para), linked with progression of ischemic induced necrosis of the myocardial ischemic reperfusion injury (page 356 last para 2.1), higher Il8 in patients with ventricular fibrillation complicating myocardial infarction (page 356 2.2 second para)’. IL8 is a powerful independent predictive factor for cardiovascular and overall mortality in patients with end stage renal disease. IL8 precede CAD (Coronary Artery Disease). ‘
The authors concluded that increased serum levels of IL8 after PCU (percutaneous coronary intervention) are probably a predictor of the development of heart failure’ (page 356 2nd column 2nd para). Elevated Il8 in patients with ‘cardiogenic shock or end stage heart disease’ (p356 2nd column mid-way down)
Page 357 1st column 2nd bottom para: The highest levels of IL8 were detected at the time of admission to the coronary care unit and thereafter decreased significantly. Il8 has also been assessed as a marker of outcome in patients resuscitated following cardiopulmonary arrest.
Page 357 top 2nd column 1st para: ‘The authors concluded that ‘significant’ elevation of S100B and Il8 serum levels 12 hours after cardiac arrest suggest that primary brain damage and systemic inflammatory response are comparably serious with the damage involved in traumatic brain injury’.
Page 358 1st column 1st para: Increased serum levels of IL8 are correlated with an increased risk of cardiovascular disease or acute cardiovascular events.
Interleukin-6 and interleukin-8 serum levels in prognosis of hormone-dependent breast cancer.
Cytokine 2018 Feb 23. Epub 2018 Feb 23.
Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia.
Background: Increasing amount of evidence points to the importance of immunity in breast cancer. The prognostic value of cytokines and their effect on tumorigenesis remains inconsistent.
Aim: To investigate the prognostic significance of IL6 and IL8 and their association with ER and HER2 in estrogen-dependent (ER+) breast cancer.
Material And Methods: The study included 79 premenopausal women with early and locally advanced ER+ breast cancer. All patients received adjuvant hormonal therapy: tamoxifen alone (56/79) or combination with LHRH agonist goserelin (23/79). IL6 and IL8 serum protein levels were measured by ELISA. Cox proportional hazards regression analysis was implemented for prognostic evaluation of the data categorized based on metastasis outcome.
Results: IL6 associated with good (P = 0.001, HR = 0.05) and IL8 with poor disease outcome (P = 0.03, HR = 2.5) in the whole group of patients. Multivariate analyses highlighted IL6 as the independent prognostic factor (P = 0.001, HR = 0.0007). When patients were classified according to ER or HER2 status, IL6 did not have prognostic significance in ERand ERsubgroups, while IL8 retained prognostic significance only in the ERsubgroup (P = 0.04, HR = 2.8). IL6 was significant in both HER2- (P = 0.001, HR = 0.05) and HER2+ subgroups (P = 0.002, HR = 0.04), while IL8 retained its prognostic significance only in the HER2+ subgroup (P = 0.001, HR = 77.8).
Conclusions: This study contributes to the clarification of the prognostic performance of IL6 and IL8 by providing their first prognostic evaluation in the homogenized ER+ breast cancer patient group. IL6 was indicated as a marker of favorable, whereas IL8 was a marker of unfavorable disease outcome.
Clinical significance of serum interleukin-8 and soluble tumor necrosis factor-like weak inducer of apoptosis levels in patients with diabetic nephropathy.
J Diabetes Investig 2018 Feb 28. Epub 2018 Feb 28.
Department of Endocrinology, The First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People's Hospital), Jiao Zuo, China.
Introduction: Recent studies suggest that chronic inflammatory responses are important in the development of diabetic nephropathy (DN). Various inflammatory and angiogenesis molecules affect the pathogenesis and progression of DN. Inflammation damages the microcirculation and causes kidney damage. In this study, we studied changes in interleukin-8 (IL-8) and soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels in patients with diabetic nephropathy (DN) and investigated the clinical significance of these two inflammatory factors.
Materials And Methods: Subjects were categorized into healthy controls (n = 30, NC group) and patients with type 2 diabetes mellitus (n = 124, T2DM). The T2DM group was further subdivided into the normoalbuminuria (n = 34, NMAU), microalbuminuria (n = 46, MAU) and proteinuria (n = 44, MaAU) groups. Patients with DN were included in the MAU and MaAU groups. Total cholesterol, triglyceride, low-density lipoprotein cholesterol, glycosylated hemoglobin, fasting blood glucose, 2-hour postprandial blood glucose, blood urea nitrogen, serum creatinine, 24-hour urine microalbumin (MAL), IL-8, and sTWEAK levels were measured. Logistic regression was used to analyze the factors associated with proteinuria.
Results: In the NC, NMAU, MAU, and MaAU groups, we found that IL-8 levels increased whereas sTWEAK levels decreased (P <0.05). IL-8 might be an independent risk factor and serum sTWEAK a protective factor for MAU and MaAU. Serum levels of sTWEAK, IL-8, and MAL were significantly correlated in the MAU and MaAU groups.
Interleukin-8 favors pro-inflammatory activity of human monocytes/macrophages.
Int Immunopharmacol 2018 Jan 27;56:217-221. Epub 2018 Jan 27.
Immanuel Kant Baltic Federal University, 14 A.Nevskogo St., Kaliningrad 236016, Russia. Electronic address:
Interleukin-8 (IL-8, CXCL8) belongs to major chemokines to stimulate migration of neutrophils and monocytes/macrophages (Mc/Mphs) into the inflammation sites. We studied the direct effects of IL-8 on the functionality of human Mc/Mphs in vitro. CD14-positive cells were isolated from human peripheral blood mononuclear cells (PBMCs) by positive magnetic separation and were further cultured with or without lipopolysaccharide (LPS, 1.0 μg/ml) for 24 h. We showed that upon LPS activation of Mc/Mphs, IL-8 reduced markedly both the percentages and median fluorescence intensity (MFI) of CD16 (FcγRIII)-positive cells among CD14cells, as well as in cells that reduced the expression of СD14 during their culturing. IL-8 was also found to be capable of reducing the expression of СD124 (IL-4 receptor subunit alpha, IL-4RA), with concomitant enhancement of the expression of both CD119 (interferon-gamma receptor 1) and CD197 (CCR7) in Mph cells. In addition, IL-8 up-regulated production of IL-6 and IL-1β [but not tumor necrosis factor-α (TNF-α) and IL-10] by activated Mc/Mphs. Our results suggest the ability for IL-8 to directly favor pro-inflammatory M1-type Mph activity.
* Hypoxia, IL8 and Acidity Contribute To Cancer Growth (UHMS 2003)
** IL8 with IL1, 6 and TNF-α have been linked with tumor-associated macrophages (TAM) in promoting tumor angiogenesis.
* In vivo tumorigenesis analysis further proved that tumor tissues from patients with higher serum IL-8 levels grew faster than those with lower IL-8 levels.
Chronic Pancreatitis Associated Acute Respiratory Failure.
MOJ Immunol 2017 8;5(2). Epub 2017 Feb 8.
Department of Medicine and Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, USA.
Pancreatitis is a condition characterized by parenchymal inflammation of the pancreas, which is often associated with lung injury due to low level of oxygen and the condition is termed as acute pancreatitis-associated lung injury (APALI). Clinical reports indicated that ~ 20% to 50% of patients from low oxygen levels in blood with acute respiratory distress syndrome (ARDS). ARDS is a severe form of acute lung injury (ALI), a pulmonary disease with impaired airflow making patients difficult to breathe. ALI is frequently observed in patients with severe acute pancreatitis. Approximately one third of severe pancreatitis patients develop acute lung injury and acute respiratory distress syndrome that account for 60% of all deaths within the first week. The major causes of ALI and ARDS are sepsis, trauma, aspiration, multiple blood transfusion, and most importantly acute pancreatitis. The molecular mechanisms of ALI and ARDS are still not well explored, but available reports indicate the involvement of several pro-inflammatory mediators including cytokines (TNF-α, IL-1β, IL-6) and chemokines [like interleukin-8 (IL-8) and macrophage inhibitory factor (MIF)], as well as macrophage polarization regulating the migration and pulmonary infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the pulmonary parenchyma. Acute lung injury and acute respiratory distress syndrome in acute pancreatitis remains an unsolved issue and needs more research and resources to develop effective treatments and therapies. However, recent efforts have tested several molecules in an experimental model and showed promising results as a treatment option. The current review summarized the mechanism that is operational in pancreatitis-associated acute respiratory failure and respiratory distress syndrome in patients and current treatment options.
Acta Sci Pol Technol Aliment. 2017 Jan-Mar;16(1):83-91. doi: 10.17306/J.AFS.2017.0442.
The genetic basis of obesity complications.
Intensive research is currently being performed into the genetic background of excess body mass compli- cations such as diabetes, cardiovascular disorders, especially atherosclerosis and coronary heart disease. Chronic inflammation is an important process in the pathogenesis of obesity, wherein there is an aberrant ex- pression of genes encoding adipokines. Visceral tissue is characterized by a higher expression and secretion of interleukin-8, interleukin-1ß and plasminogen activator inhibitor 1 in the subcutaneous tissue secretion of leptin prevails. An important complication of obesity is obstructive sleep apnea, often observed in Prader- Willi syndrome. The genetic background of sleep apnea may be a polymorphism of the SREBF1 gene. The consequence of excess body mass is metabolic syndrome, which may be related to the occurrence of the rs926198 variant of gene encoding caveolin-1. The genes of transcription factor TCF7L2 and PPAR-γ2 take part in the pathogenesis of diabetes development. It has been demonstrated that oncogenes FOS, FOSB, and JUN may be co-responsible not only for obesity but also for osteoporosis and colorectal cancer. It has been shown that weight loss causes a modification in the expression of about 100 genes involved in the production of substances such as cytokines and other responsible for chronic inflammation in obesity. In future studies on the complications of obesity, such scientific disciplines as proteomics, peptidomics, metabolomics and transcriptomics should be used. The aim of this study is to present the current state of knowledge about the genetic basis of obesity complications.
Pancreas. 2016 May-Jun;45(5):671-8. doi: 10.1097/MPA.0000000000000520.
IL-8-Positive Tumor-Infiltrating Inflammatory Cells Are a Novel Prognostic Marker in Pancreatic Ductal Adenocarcinoma Patients.
Tumor-infiltrating inflammatory cells (TIICs) in pancreatic ductal adenocarcinoma (PDAC) are reported to initiate and exacerbate invasion and metastasis. Interleukin-8 (IL-8), a proinflammatory cytokine, is expressed in both neoplastic cells and TIICs in PDAC tissues and increased in patient serum. The aim of this study is to evaluate the values of IL-8 expression profiles in tumor tissues and predict the source of serum IL-8 in PDAC patients.
We used 2 independent groups of PDAC patient samples that included 240 cases. Tissue expression profiles of cytokines were evaluated with immunohistochemistry and serum levels with human IL-8 assay. The prognostic values of the variables were assessed by Kaplan-Meier or Cox regression analysis.
Higher levels of IL-8-positive TIICs but not tumor cells in PDAC patients correlated with worse prognosis (P = 0.009) and higher blood serum IL-8 levels (P = 0.002). Controlling other independent factors, the relative hazard ratio for PDAC with higher IL-8-positive TIIC levels compared with those with lower TIIC levels was 1.588 (95% confidence interval, 1.04-2.42).
Higher IL-8-positive TIIC levels in PDAC tumors indicate poorer prognosis and positively correlate with serum IL-8 concentrations and vice versa. These data suggested that IL-8 might have a potential target for PDAC therapies.
Br J Cancer. 2015 Mar 31;112(7):1199-205. doi: 10.1038/bjc.2015.73.
Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours.
Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study.
Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed.
Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4.
Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.
Oncol Lett. 2017 Feb;13(2):567-572. doi: 10.3892/ol.2016.5511. Epub 2016 Dec 16.
Effect of targeted silencing of IL-8 on in vitro migration and invasion of SKOV3 ovarian cancer cells.
The aim of the study was to determine whether interleukin-8 (IL-8) affects human SKOV3 ovarian cancer cell migration and invasion by targeting silencing of IL-8 expression. Silencing small-interfering RNA (siRNA) targeting IL-8 gene was constructed to infect SKOV3 cells by lentiviral vector. The expression of IL-8 and p-nuclear factor (NF)-κB protein was detected by western blot analysis. The wound scratch and Transwell tests were used to assay the cell migration and invasiveness of SKOV3 cells infected with lentiviral vector targeting IL-8 gene siRNA. The levels of IL-8 protein expressed by SKOV3 cells infected by lentiviral vector targeting IL-8 gene siRNA decreased by 72.3%. IL-8 (50 ng/ml) increased the ability of SKOV3 cells to suppress cell migration (p<0.01). Cisplatin and silencing of IL-8 achieved the ability to inhibit SKOV3 cell invasion (p<0.01), and 100 ng/ml concentration of IL-8 enhanced the ability of SKOV3 invasion (p<0.01). Silencing of IL-8 to a certain extent reduced the expression of p-NF-κB proteins, but it was not statistically significant. In conclusion, silencing of IL-8 may inhibit the migration and invasion of SKOV3 cells, which may be independent of the p-NF-κB protein.
Oncoimmunology. 2017 Jan 3;6(2):e1265719. doi: 10.1080/2162402X.2016.1265719. eCollection 2017.
High baseline levels of interleukin-8 in leukocytes and urine predict tumor recurrence in non-muscle invasive bladder cancer patients receiving bacillus Calmette-Guerin therapy: A long-term survival analysis.
Bacillus Calmette-Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) can significantly reduce the risk of recurrence and progression. However, BCG therapy may fail in up to a half of treated patients and may also cause toxicities. Biomarkers to predict the effectiveness of BCG therapy are desired to pre-select patients for BCG therapy to maximize efficacy while avoid unnecessary toxicity. Twelve cytokines were measured in 100 blood and 112 urine samples using cytokine antibody array and correlated with recurrence-free survival in overall and BCG-treated NMIBC patients.
Of the 12 cytokines, interleukin (IL) -2, IL-8, IL-10, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-γ were measurable in more than 30% of peripheral blood leukocyte (PBL) samples. Only IL-8 in PBL was found to be significantly associated with tumor recurrence, especially in those who receiving BCG therapy (hazard ratio [HR] = 4.24; 95% confidence interval [95%CI] = 1.65-10.88; p = 0.003). The median recurrence-free survival time for BCG-treated patients with high baseline IL-8 levels were much shorter than those with low IL-8 levels (7.9 vs. >78.4 mo, p = 0.004). Furthermore, consistent associations between urinary IL-8 levels and tumor recurrence in patients receiving BCG therapy were observed in 58 pre-BCG and 54 long-term post-BCG-treated urine samples (both p ≤ 0.005). High urinary baseline IL-8 level also predicted shorter time to tumor recurrence in NMIBC patients (both p ≤ 0.004). By using antibody array-based technology in two separate cohorts of NMIBC patients, we found that PBL and urinary baseline IL-8 levels were significantly associated with tumor recurrence after BCG therapy.
Medicine (Baltimore). 2017 Feb;96(5):e5926
Serum interleukin-6 is associated with pancreatic ductal adenocarcinoma progression pattern.
Several reports showed that interleukin-6 (IL-6) or -8 (IL-8) might be useful inflammatory biomarkers for pancreatic ductal adenocarcinoma (PDAC), although these clinical impact is still open to debate. The aim of this study was to elucidate whether serum levels of IL-6 and IL-8 at diagnosis could predict the tumor progression pattern of PDAC, especially in extensive hepatic metastasis.According to the tumor burden of hepatic metastasis at the last follow-up, tumor progression pattern was defined as follows: no or limited (unilobar involvement and 5 or less in the within liver, limited group) and extensive hepatic metastasis (bilobar or more than 5, progressed group). Fifty-three PDAC patients with initially no or limited hepatic metastasis were enrolled retrospectively.Around 42 (79.2%) were included in the limited and 11 (20.8%) in the progressed group. The median serum level of IL-6 in the progressed group was elevated significantly compared with the limited group. However, the median serum level of IL-8 was not. Furthermore, multivariate analysis revealed that the elevated serum level of IL-6 was an independent risk factor for progression to extensive hepatic metastasis (odds ratio 1.928, 95% confidence interval 1.131-3.365, P = 0.019), but IL-8 was not. However, higher IL-6 did not predict shorter survival.High serum IL-6 can be an independent risk factor for progression to extensive hepatic metastasis in PDAC patients.
J Pathol. 2017 Apr;241(5):638-648. doi: 10.1002/path.4868.
Loss of dual-specificity phosphatase-2 promotes angiogenesis and metastasis via up-regulation of interleukin-8 in colon cancer.
Dual-specificity phosphatase 2 (DUSP2) is a negative regulator of mitogen-activated protein kinases. Our previous study showed that DUSP2 expression is down-regulated in many human cancers and loss of DUSP2 promotes cancer progression; however, the underlying mechanism remains largely uncharacterized. Herein, we found that loss of DUSP2 induces angiogenesis, while forced expression of DUSP2 inhibits microvessel formation in xenografted mouse tumours. Genome-wide screening of expression profiles, and meta-analysis of clinical data, identified that the level of interleukin-8 (IL-8) correlated negatively with that of DUSP2, suggesting that it may be a downstream target of DUSP2. Molecular characterization revealed that DUSP2 inversely regulates IL-8 expression, mediated by ERK1/2 and C/EBPα-dependent transcriptional regulation. Further study showed that hypoxia-induced IL-8 expression in cancer cells is also mediated via down-regulation of DUSP2. Treatment with the IL-8 receptor inhibitor reparixin or knockdown of IL-8 in cancer cells abolished angiogenesis induced by loss of DUSP2. Functionally, knockdown of DUSP2 enhanced tumour growth and metastasis, which were abolished by treatment with reparixin or knockdown of IL-8 in an orthotopic mouse model. Taken together, our results demonstrate that hypoxia inhibits DUSP2 expression in colon cancer, leading to up-regulation of IL-8, which facilitates angiogenesis and tumour metastasis. Our findings suggest that blocking hypoxia-DUSP2-IL-8 signalling may be a plausible approach for therapeutic intervention in cancer.