Inflammatory cytokines IL-32 and IL-17 have common signaling intermediates despite differential dependence on TNF-receptor 1.
ABSTRACT Cytokines IL-32 and IL-17 are emerging as critical players in the pathophysiology of immune-mediated chronic inflammatory diseases. It has been speculated that the molecular mechanisms governing IL-32- and IL-17-mediated cellular responses are differentially dependent on the TNF pathway. In this study, kinome analysis demonstrated that following stimulation with cytokine IL-32, but not IL-17, there was increased phosphorylation of a peptide target corresponding to TNF-R1. Consistent with this observation, blocking TNF-R1 resulted in a suppression of IL-32-induced downstream responses, indicating that IL-32-mediated activity may be dependent on TNF-R1. In contrast, blocking TNF-R1 did not affect IL-17-induced downstream responses. Kinome analysis also implicated p300 (transcriptional coactivator) and death-associated protein kinase-1 (DAPK-1) as signaling intermediates for both IL-32 and IL-17. Phosphorylation of p300 and DAPK-1 upon stimulation with either IL-32 or IL-17 was confirmed by immunoblots. The presence of common targets was supported by results demonstrating similar downstream responses induced in the presence of IL-32 and IL-17, such as transcriptional responses and the direct activation of NF-κB. Furthermore, knockdown of p300 and DAPK-1 altered downstream responses induced by IL-32 and IL-17, and impacted certain cellular responses induced by TNF-α and IL-1β. We hypothesize that p300 and DAPK-1 represent nodes where the inflammatory networks of IL-32 and IL-17 overlap, and that these proteins would affect both TNF-R1-dependent and -independent pathways. Therefore, p300 and DAPK-1 are viable potential therapeutic targets for chronic inflammatory diseases.
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ABSTRACT: Cytokines have always been of great interest due to their vast potential and participation in the progression and pathogenesis of various ailments. Interleukin-32 (IL-32) is a recently identified cytokine, whose gene is located on human chromosome 16 p13.3, with eight exons and six splice variants (IL-32¿ to IL-32¿). IL-32¿, the most abundant form, is secreted by different types of cells including T cells, natural killer (NK) cells, monocytes, endothelial cells and epithelial cells. It acts as a preferential mediator and effector of abnormal immune responses to multiple inflammatory and auto immune diseases including rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), etc. It was found to stimulate the induction of various chemokines, pro-inflammatory cytokines including IL-1ß, IL-6, IL-8, TNF-¿ and macrophage inflammatory protein-2 (MIP-2). Hence, IL-32 mediates the crucial interplay among immune system and body cells during pathogenesis of various insults. The aim of the present effort is to summarize the role, mechanism of pathogenesis and potential therapeutic applications of IL-32 in different systemic infections and diseased conditions.European journal of medical research 01/2015; 20(1):7. DOI:10.1186/s40001-015-0083-y · 1.40 Impact Factor
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ABSTRACT: AimPoorly-controlled glycemic status in type 2 diabetes mellitus (T2DM) is suggested to play a role in the periodontal inflammatory process by aggregating the local cytokine response. Our objectives were to profile salivary interleukin (IL)-17 and tumor necrosis factor (TNF)-α levels in subjects with T2DM and to examine their relevance for the periodontal health status and glycemic control levels.Methods Unstimulated whole saliva samples, together with full-mouth periodontal recordings [plaque index (PI), bleeding on probing (BOP %), gingival index (GI), probing pocket depth (PPD), and clinical attachment level (CAL)], were collected from 123 subjects with T2DM. Additionally, demographic and general health parameters, including fasting blood glucose, glycated hemoglobin (HbA1c), were collected. Salivary IL-17 and TNF-α concentrations were analyzed using the Lumina®-map™ technique.ResultsSubjects with poorly-controlled T2DM (HbA1c ≥7) had elevated serum triglyceride (p<0.001) concentration as well as elevated scores of BOP % (p=0.014), PI (p=0.048), GI (p=0.033), and CAL (p=0.003) in comparison to those of well-controlled T2DM (HbA1c<7). When the subjects with detectable salivary IL-17 were categorized in textiles, the scores of PPD and BOP %, and salivary TNF-α concentrations were significantly elevated in the highest (p=0.007, p=0.002 and p<0.001, respectively) and middle (p=0.052, p=0.022, and p=0.003, respectively) textiles compared to subjects with non-detectable salivary IL-17. The adjusted association between PPD measurements and salivary IL-17 concentrations was significant (p=0.008).Conclusions Poorly-controlled glycemic status relates to the severity of periodontal disease in T2DM. The association between PPD and IL-17 in saliva, however, is independent from the effect of glycemic status.Journal of Diabetes 10/2014; DOI:10.1111/1753-0407.12228 · 2.35 Impact Factor
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ABSTRACT: IL-32β is highly expressed and increases the migration and invasion of gastric, lung, and breast cancer cells. Since IL-32 enhances VEGF production under hypoxic conditions, whether IL-32β is regulated by hypoxia was examined. Hypoxic conditions and a mimetic chemical CoCl2 enhanced IL-32β production. When cells were treated with various inhibitors of ROS generation to prevent hypoxia-induced ROS function, IL-32β production was suppressed by both NADPH oxidase and mitochondrial ROS inhibitors. IL-32β translocated to the mitochondria under hypoxic conditions, where it was associated with mitochondrial biogenesis. Thus, whether hypoxia-induced IL-32β is associated with oxidative phosphorylation (OXPHOS) or glycolysis was examined. Glycolysis under aerobic and anaerobic conditions is impaired in IL-32β-depleted cells, and the hypoxia-induced IL-32β increased glycolysis through activation of lactate dehydrogenase. Src is also known to increase lactate dehydrogenase activity, and the hypoxia-induced IL-32β was found to stimulate Src activation by inhibiting the dephosphorylation of Src. These findings revealed that a hypoxia-ROS-IL-32β-Src-glycolysis pathway is associated with the regulation of cancer cell metabolism. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.Cancer Letters 11/2014; 356(2). DOI:10.1016/j.canlet.2014.10.030 · 5.02 Impact Factor