Inflammasome activation and IL-1β and IL-18 processing during infection

Interleukin-1β (IL-1β) and IL-18 contribute to host defense against infection by augmenting antimicrobial properties of phagocytes and initiating Th1 and Th17 adaptive immune responses. Protein complexes called inflammasomes activate intracellular caspase-1 autocatalytically, which cleaves the inactive precursors of IL-1β and IL-18 into bioactive cytokines. In this review, we discuss the controversies regarding inflammasome activation and the role of the inflammasome during infection. We highlight alternative mechanisms for processing IL-1β and IL-18 during infection, which involve extracellular cleavage of the inactive cytokines by neutrophil-derived serine proteases or proteases released from cytotoxic T cells.     

IL-4 and IL-13 receptors: are they one and the same?

Interleukin 4 (IL-4) and IL-13 share several biological properties, suggesting that they also share a common receptor or receptor component. Indeed, as discussed here by Robin Callard and colleagues, the IL-13 receptor appears to be a functional receptor for IL-4.     

Antimicrobial Agents Induce Monocytes to Release IL-1α, IL-6, and Tnf and Induce Lymphocytes to Release IL-4 and TNFτ

Abstract

Evaluation was carried out on the action of different antibiotics on the release of cytokines. Experiments were done in vitro on monocytes and on human lymphocytes. Results show that the majority of the antibiotics tested are able to induce the release of one or more cytokines from their respective producing cells. Among the β-lactams the most active were the cephalosporins (cephalexin, cefamandol, ceftazidin, and a sulbactam-ampxcillin combination) in inducing the release of TNF, IL-1α and IL-6 from monocytes, and releasing IL-4 and IFN-τ from lymphocytes. The sulbactam-ampicillin combination and cefamandole were extremely active in the production of IFN-τ. Among the lincosamides, clindamycine notably stimulated the release of TNF and IL-6, while lincomycine induced a notable increment of IL-4 from monocytes. Teicoplanin is a very strong inducer of TNF, IL-1α and IL-6.     

IL-2, IFN-γ, and IL-12 Gene Polymorphisms and Susceptibility to Multiple Sclerosis

Background  

Multiple sclerosis (MS) is a multifactorial disease. Positive genetic background could predispose individuals to this chronic disabling disease. In order to investigate the role of some proinflammatory cytokines (interleukin (IL)-2, IL-12, and interferon-gamma (IFN-γ)) as a risk factor for MS, this study was performed.     

Expression of IL-5 、IL-15 and IL-18 in sera of patients with allergic rhinitis and/or bronchial asthma

Objective To explore the effect of IL-5, IL-15 and IL-18 in pathogenesis of patient with allergic rhinitis (AR) and bronchial asthma. Methods The serum samples were obtained from 33 patients with asthma,35 patients with AR, 35 patients with AR and BA, and 35 controls. The serum levels of IL-5,IL-15 and IL-18 were measured by ELISA. Results The levels of IL-5,IL-15 and IL-18 were greatly increased in all patient groups than the control group (P＜0.01). The levels of IL-5 ,IL-15 and IL-18 were greatly increased in AR and BA group than the group of BA and the group of AR.The level of IL-5 in the group of AR was higher than that in the group of BA.(P=0.003). The level of IL-18 in the group of BA was higher than that in the group of AR( P=0.001 ). Conclusions IL-5 ,IL-15 and IL-18play a prominent role in the pathogenesis of AR and BA. Inflammations in the group of AR accompanying BA group are much higher. there is difference in inflammations between BA and AR.     

IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not

Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-γ nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-γ and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-α potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations. Kerstin Wolk and Harald S. Haugen equally contributed to this work.     

IL-33 enhances macrophage release of IL-1β and promotes pain and inflammation in gouty arthritis

Inflammation Research - To investigate the role of IL-33 in gouty arthritis. 174 Balb/c (wild-type) and 54 ST2?/? mice were used in this study. In vitro experiments were conducted in...     

Serum Levels of IL-6, IL-10, IL-12, IL-17 and IFN-γ and Their Association with Markers of Bone Metabolism in Vitamin D-Deficient Female Students

Different studies have shown the regulatory effects of vitamin D₃ on the immune system and bone metabolism. Regarding the effects of vitamin D on immune cells and the importance of cytokines on bone metabolism, we assessed the association between serum levels of interleukin (IL)-6, IL-10, IL-12, IL-17 and IFN-γ cytokines and bone metabolism markers (Ca, P, PTH, ALP) in female students with vitamin D deficiency compared with control group. A total of 100 subjects with 25-hydroxy vitamin D₃ (25-(OH) D₃) deficiency were selected as case and 100 subjects with sufficient 25-hydroxy vitamin D₃ (25-(OH) D₃) were selected as the control group. The serum levels of IL-6, IL-10, IL-12, IL-17 and IFN-γ were measured by ELISA method. Ionized Ca, PTH, P, ALP levels were also determined in all participants. The results showed a statistically significant positive correlation between the levels of ALP with IFN-γ, PTH with IL-17 and a significant negative correlation between P with IL-10 in vitamin D deficient group. The results suggest that IL-17, IFN-γ and IL-10 are important mediators of bone metabolism and vitamin D affect bone metabolism, at least in part, through immune system. In addition, not only vitamin D affect bone metabolism but also modulates immune responses.     

Human β-defensin-2 enhances IFN-γ and IL-10 production and suppresses IL-17 production in T cells

Psoriasis is an inflammatory dermatosis with enhanced expression of hBD-2 in keratinocytes and infiltration of cytokine-producing T cells, which in turn, up- or down-regulate hBD-2 expression. We determined the serum levels of hBD-2 and cytokines in psoriasis patients and analyzed the effects of hBD-2 on cytokine production in human peripheral blood T cells. Serum hBD-2 levels in patients were higher than those in controls and correlated with PASI, serum IFN-γ, and IL-10 levels and correlated inversely with serum IL-17 levels. IFN-γ, IL-17, IL-22, TNF-α, IL-1β, and IL-6 enhanced, and IL-10, IL-4, and IL-13 suppressed hBD-2 secretion from keratinocytes. hBD-2 enhanced secretion and mRNA levels of IFN-γ, TNF-α, IL-10, IL-1β, IL-6, and IL-22 and reduced those of IL-17 in CD3/28-stimulated T cells. These effects of hBD-2 were counteracted by PTX. hBD-2 induced phosphorylation of JNK, ERK, and Akt in T cells. Inhibitors of these signals attenuated hBD-2-induced production of IFN-γ, TNF-α, IL-10, IL-1β, IL-6, and IL-22. hBD-2 suppressed phosphorylation of STAT3 and enhanced expression of SOCS3 in CD3/28-stimulated T cells. siRNA against SOCS3 reversed hBD-2-induced suppression of IL-17 production and STAT3 phosphorylation. JNK and MEK inhibitors suppressed hBD-2-induced expression of SOCS3. In conclusion, hBD-2 may bind PTX-sensitive GPCR(s) on T cells and act as a stimulator by enhancing IFN-γ, TNF-α, IL-1β, IL-6, and IL-22 production via JNK, MEK/ERK, and PI3K/Akt and as a regulator by suppressing IL-17 production via SOCS3 or by stimulating IL-10 production.     

IL-10— and IL-20—Expressing Epithelial and Inflammatory Cells are Increased in Patients with Ulcerative Colitis

Interleukin (IL)-20, a pro-inflammatory cytokine, is a recently discovered member of the IL-10 family. This cytokine has been described in inflammatory diseases such as psoriasis and asthma. However, IL-20 expression in ulcerative colitis (UC) patients has not been yet described. The aim of this study was to evaluate IL-20 and IL-10 gene and protein expression and their receptors in the mucosa from UC patients. Forty UC patients and 18 non-inflamed controls were studied. IL-10, IL-20, IL-10R1, IL-10R2, IL-20R1 and IL-20R2 gene expression was determined by real time RT-PCR in colonic biopsies. Protein expression was evaluated by immunohistochemistry. Patients in remission had significantly higher IL-10 gene expression in mucosa compared with active patients and controls. Conversely, IL-10R1/B gene expression was decreased in remission compared with active UC patients and controls. IL-20 gene expression was lower in colonic mucosa from UC patients in remission compared with controls and active patients. IL-20R1/B mRNA expression was higher in remission compared with active UC patients and controls. IHQ analysis showed an increased IL-10—, IL-20—, and IL-20R2—producing cells in active UC patients. IL-10—, IL-20— and IL-20R2—expressing epithelial and inflammatory cells were increased in active UC patients, meanwhile IL-20R1 was up-regulated only on inflammatory infiltrates vs. controls. This is the first depiction of the presence of IL-20 and its receptors in UC. Much remains to be learned however, about the pathogenic mechanisms that lead to IBD. This cytokine/receptor imbalance may be implicated in the pathogenesis of UC.     

IL-7 Receptor Blockade Inhibits IL-17-Producing γδ Cells and Suppresses Melanoma Development

In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, wild-type mice are inoculated with melanoma cell line B16-F10 (1?×?10⁶/mouse) and treated with anti-IL-7R antibody or recombined mouse IL-7 (rmIL-7). Growth of melanoma cell line B16-F10 was significantly inhibited in anti-IL-7R antibody-treated mice and markedly promoted in rmIL-7-treated mice compared with that in control. A decreased number of myeloid-derived suppressor cells (MDSCs) and γδ cells in tumor tissues were detected from anti-IL-7R antibody-treated mice. Next, administration of the anti-IL-7R antibody significantly blocked the enrichment in IL-17⁺ γδ cells in tumor. Moreover, in our further experiment, promoted melanoma development induced by rmIL-7 was abrogated with p-Stat3 inhibitor. The increased proportion and absolute number of IL-17-producing γδ27^? cell induced by rmIL-7 were also abolished with the p-Stat3 inhibitor administration, and the suppressed melanoma development induced by anti-IL-7R antibody treatment was reversed with additional use of Ad-IL-17. In conclusion, IL-7/IL-7R-Stat3-IL-17 pathway promotes melanoma growth, and inhibition of IL-7/IL-7R-Stat3-IL-17 pathway may contribute to tumor growth in murine models of melanoma.     

Cytokine Profile in Gout: Inflammation Driven by IL-6 and IL-18?

Introduction: Gout is considered to be an autoinflammatory disease and the presence of monosodium urate (MSU) crystals stimulates activation of NPRL3 inflammasome and subsequently caspase-1, generating production of active IL-1β and IL-18. However, the association between serum cytokines levels and clinical manifestations of the disease is not yet well understood. We evaluated the serum profile of proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-17A, IL-18, IL-22, and IL-23) and described their relationship with clinical and laboratory data.

Methodology: Thirty-nine male patients with gout (GG) were assessed for clinical and laboratory variables and cytokine levels were measured by ELISA. For the purposes of comparison, 34 males with no previous history of arthritis were also included in the study (CG).

Results: Seventeen participants (43%) exhibited active arthritis on evaluation. Levels of IL-18 were significantly higher in patients in relation to the CG (p = 0.0013). No statistically significant differences were found between the GG and CG for the other measured cytokines. There was a moderate correlation between IL-18 and ESR (R = 0.43, p = 0.0073), CRP (R = 0.47, p = 0.0025), and serum levels of IL-6 (R = 0.36, p = 0.023). An association was observed between serum levels of IL-6 and the presence of tophi (p = 0.005) and deformities (p = 0.0008), as well as a correlation between this cytokine and ESR (R = 0.41, p = 0.011) and CRP (R = 0.48, p = 0.02).

Conclusions: IL-18 is associated with inflammatory activity in gout, as well as with IL-6 levels, while IL-6 is associated with clinical and laboratory activity, the presence of tophi and articular deformities, and may be a prognostic marker of this pathology.     

Function and regulation of IL-1α in inflammatory diseases and cancer

The interleukin (IL)-1 family of cytokines is currently comprised of 11 members that have pleiotropic functions in inflammation and cancer. IL-1α and IL-1β were the first members of the IL-1 family to be described, and both signal via the same receptor, IL-1R. Over the last decade, much progress has been made in our understanding of biogenesis of IL-1β and its functions in human diseases. Studies from our laboratory and others have highlighted the critical role of nod-like receptors (NLRs) and multi-protein complexes known as inflammasomes in the regulation of IL-1β maturation. Recent studies have increased our appreciation of the role played by IL-1α in inflammatory diseases and cancer. However, the mechanisms that regulate the production of IL-1α and its bioavailability are relatively understudied. In this review, we summarize the distinctive roles played by IL-1α in inflammatory diseases and cancer. We also discuss our current knowledge about the mechanisms that control IL-1α biogenesis and activity, and the major unanswered questions in its biology.     

Blood Serum Levels of IL-2, IL-6, IL-8, TNF-α and IL-1β in Patients on Maintenance Hemodialysis

Cytokines are essential mediators of immune response and inflammatory reactions. Patients with chronic renal failure (CRF) commonly present with abnormalities of immune function related with impaired kidney function and the accumulation of uremic toxins in addition to bioincompatibility of dialyzer membranes. During a hemodialysis (HD) session, cytokines are released mainly by monocytes activated by endotoxin-type compounds in dialyzer fluid, complement factors and direct contact with dialyzer membrane. The study included 15 CRF patients, aged 36.4±2.9 years, on regular HD maintenance therapy for mean 68±10 months and 15 healthy controls. It was designed to assess serum levels of a panel of inflammatory cytokines: IL-1β, IL-2, IL-6, IL-8 and TNF-αin CRF patients on regular maintenance HD before, 20, 60 and 240 minutes of a single HD session in parallel with C-reactive protein (CRP) as an additional parameter. CRP concentration was increased in HD patients when compared with healthy controls. The concentrations of IL-1, IL-6, IL-8 and TNF-αwere increased, whereas the serum level of IL-2 was not altered during a single HD session.     

Evaluation of serum levels of IL-6, TNF-α, IL-10, IL-2 and IL-4 in patients with chronic hepatitis

Background

Changes in various cytokine activities have been reported during both HBV and HCV infections, while an imbalance of pro-inflammatory and anti-inflammatory cytokine production influences their immunopathogenesis. The aims of the present study are (a) to measure serum levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin-10 (IL-10), interleukin-2 (IL-2) and interleukin-4 (IL-4) in a sample of patients affected either by chronic HBV infection or by chronic HCV infection and in healthy controls (b) to correlate serum levels of IL-6, TNF-α, IL-10, IL-2 and IL-4 with biochemical markers of liver disease and (c) to evaluate differences of the aforementioned cytokines between HBV and HCV patients, as well as between patients and healthy controls.

Methods

The study population consisted of 50 patients with chronic hepatitis B, 40 patients with chronic hepatitis C and 30 healthy controls aged between 28 and 75 years. Biochemical markers of liver disease were evaluated by routine methods approved by IFCC. Serum concentrations of IL-6, TNF-α, IL-10, IL-2 and IL-4 were determined with the Human Cytokine/Chemokine Panel I Merck Millipore.

Results

HBV patients showed statistically significant difference in TNF-α and IL-2 levels, versus healthy controls. HCV patients showed statistically significant difference in TNF-α, IL-10 and IL-2 levels versus healthy controls. IL10 and IL-2 levels were significantly different between HBV and HCV patients.

Conclusions

This study evaluated the serum cytokine levels (IL-6, TNF-α, IL-10, IL-2 and IL-4) of chronic hepatitis B or C patients, as well as the differences in such levels between patients and healthy controls. Correlations of cytokine levels with biochemical markers of liver disease were also observed, reflecting the degree of activity of the inflammatory process in the liver.     

Differential regulation of TNFα, IL-1β, IL-6, IL-8, TNFβ, and IL-10 by pentoxifylline

Pentoxifylline (PTX) is a methylxanthine drug known to inhibit the production of tumor necrosis factor-alpha (TNFα), which plays a key role in inflammation. Recent studies also revealed that other cytokines may be inhibited by PTX. We investigated PTX effects on production and mRNA expression of TNFα, IL-1β, IL-6, IL-8, TNFβ and IL-10. Cytokine release was studied in 1/10 diluted whole blood culture (WB) and in peripheral blood mononuclear cell (PBMC) culture. Cytokine production was triggered in both culture systems by endotoxin (LPS) or by phorbol ester (PMA) plus phytohemagglutinin (PHA). Our results showed that expression and production of TNFα and TNFβ were inhibited by PTX in a dose-dependent manner. Moreover, we observed that depending on the way of activating cells, PTX induced an up- or a down-regulation (in PMA+PHA or LPS stimulated cells, respectively) for IL-1 and IL-6 release. We also noted that the effects of PTX on IL-6, IL-8 and IL-10 production were different in WB and in PBMC culture. In conclusion PTX acts on cytokine in a complex manner depending on cellular environment and on the method of activation.