The IL-1 family of cytokines encompasses eleven proteins that each share a similar ␤-barrel structure and bind to Ig-like receptors. Some of the IL-1-like cytokines have been well characterised, and play key roles in the development and regulation of inflammation. Indeed, IL-1␣ (IL-1F1), IL-1␤ (IL-1F2), and IL-18 (IL-1F4) are well-known inflammatory cytokines active in the initiation of the inflammatory reaction and in driving Th1 and Th17 inflammatory responses. In contrast, IL-1 receptor antagonist (IL-1Ra, IL-1F3) and the receptor antagonist binding to IL-1Rrp2 (IL-36Ra, IL-1F5) reduce inflammation by blocking the binding of the agonist receptor ligands. In the case of IL-37 (IL-1F7), of which five different splice variants have been described, less is known of its function, and identification of the components of a heterodimeric receptor complex remains unclear. Some studies suggest that IL-37 binds to the ␣ chain of the IL-18 receptor in a non-competitive fashion, and this may explain some of the disparate biological effects that have been reported for mice deficient in the IL-18R. The biological properties of IL-37 are mainly those of down-regulating inflammation, as assessed in models where human IL-37 is expressed in mice. In this review, an overview of the role of IL-37 in the regulation of inflammation is presented. The finding that IL-37 also locates to the nucleus, as do IL-1␣ and IL-33, for receptor-independent organ/tissue-specific regulation of inflammation is also reviewed.

Decreased PTH levels and higher levels of glycemia independently contribute to lower bone turnover in elderly nursing home patients with type 2 DM. Despite higher bone mass and lower bone turnover, hip fracture risk is comparable with women without DM.

Th2 cells play a key role in directing immune responses against helminths. Additionally, Th2 cells are crucial for many types of allergic reactions. Whereas the molecular mechanisms underlying the differentiation of other types of Th cells are well understood, Th2 differentiation is still a controversial topic. IL-4 and its downstream transcription factor signal transducer and activator of transcription (STAT)6 are well-known key mediators in Th2 differentiation. The fact that Th2 cells themselves are the most potent source of IL-4 suggests that additional mechanisms promoting the initiation of Th2 differentiation exist. This article gives an overview on STAT6-dependent and -independent mechanisms involved in the process of Th2 polarization, including Notch, mTORC2, IL-2/STAT5, and Wnt. Furthermore, we emphasize the role of STAT6 not only as a transcriptional activator promoting Th2 development, but also in fine-tuning alternative signaling pathways which are involved in the initiation of Th2 polarization.

Interleukin 31 (IL-31) is a T cell-derived cytokine that signals via a hetero-dimeric receptor composed of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMRB). Although several studies have aimed to investigate IL-31-mediated effects, the biological functions of this cytokine are currently not well understood. IL-31 expression correlates with the expression of IL-4 and IL-13 and is associated with atopic dermatitis in humans, indicating that IL-31 is involved in Th2-mediated skin-inflammation. Since dendritic cells are the main activators of Th cell responses, we posed the question of whether dendritic cells express the IL-31 receptor complex and govern immune responses triggered by IL-31. In the present study, we report that primary human CD1c+ as well as monocyte-derived dendritic cells significantly up-regulate the IL-31RA receptor chain upon stimulation with interferon gamma (IFN-γ). Electrophoretic mobility shift assays, ChIP assays and siRNA-based silencing assays revealed that STAT1 is the main transcription factor involved in IFN-γ-dependent IL-31RA expression. Subsequent IL-31 stimulation resulted in a dose-dependent release of pro-inflammatory mediators, including TNF-α, IL-6, CXCL8, CCL2, CCL5 and CCL22. Since these cytokines are crucially involved in skin inflammation, we hypothesize that IL-31-specific activation of dendritic cells may be part of a positive feedback loop driving the progression of inflammatory skin diseases.

SummaryThe analysis of anti-factor VIII (FVIII) antibody-secreting cells (ASC) at different anatomic sites provides valuable information about the nature of the anti-FVIII immune response in hemophilic mice after treatment with human FVIII. An Elispot system is described that is suitable for analyzing frequencies and IgG subclasses of anti-FVIII ASC at the single-cell level. Hemophilic mice were treated with four doses of FVIII. Anti-FVIII antibodies in blood as well as anti-FVIII ASC in spleen and bone marrow were analyzed after each dose of FVIII and subsequently up to 22 weeks after termination of the FVIII treatment. Anti-FVIII ASC first appeared in the spleen where they were detectable after two intravenous doses of FVIII. Their appearance correlated with that of anti-FVIII antibodies in blood plasma. Anti- FVIII ASC in bone marrow were detectable after three doses of FVIII and were probably cells that initially formed in the spleen and subsequently migrated to the bone marrow. Whereas the frequency of anti- FVIII ASC in the spleen increased up to the fourth dose of FVIII and declined thereafter, in the bone marrow it remained constant for up to at least 22 weeks after the termination of the FVIII treatment. Titers of anti-FVIII antibodies in blood plasma increased up to the fourth dose of FVIII, then remained high constantly for 14 weeks and decreased but the antibodies were still detectable for up to at least 22 weeks after the fourth dose of FVIII. The IgG-subclass distribution of anti-FVIII ASC was similar in spleen and bone marrow and matched the subclasses of anti-FVIII antibodies in blood plasma indicating that both organs contribute to circulating antibodies in the blood.

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IL-31, a member of the IL-6 protein family, is one of the latest additions to the list of T-cell-derived cytokines. Th2 cells are regarded as a main source of IL-31, which is produced in response to stimulation by IL-4. Because the development of Th9 cells also requires IL-4 as a polarizing cytokine, the present study investigates IL-31 production in human Th9 cells compared to Th2 cells. We found that, although Th9 cells were able to release IL-31 during the first weeks of in vitro polarization, no IL-31 was detected in Th9 cultures after a final re-stimulation in the absence of polarizing cytokines. We further show that TGF-β, which is required to obtain Th9 cells in vitro, potently inhibits the release of IL-31 from Th2 cells, whereas IL-33, a cytokine associated with Th2-mediated inflammation, synergizes with IL-4 in inducing IL-31 secretion. To analyze the molecular mechanisms underlying the induction of IL-31, electrophoretic mobility shift assays, reporter gene assays and siRNA-based silencing experiments were carried out. We show that STAT6 and NF-κB are central players in mediating IL-31 expression induced by IL-4/IL-33. In addition, we identified a novel NF-κB-binding element within the Il31 promoter that mediates the enhancing effects of IL-33 on IL-4/STAT6-induced IL-31 expression in human Th2 cells. Taken together, this study shows that IL-4 is essential for the production of IL-31, whereas TGF-β significantly suppresses IL-31 expression at the mRNA and protein levels. As a consequence, in vitro-polarized Th2 cells, but not Th9 cells, are able to release IL-31.

Background: T H 17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of T H 17 cells have been described recently, which differed in their polarization requirement for IL-1b and in their cytokine repertoire. Whether these distinct T H 17 phenotypes translate into distinct T H 17 cell functions with implications for human health or disease has not been addressed yet. Objective: We hypothesized the existence of proinflammatory and anti-inflammatory human T H 17 cell functions based on the differential expression of IL-10, which is regulated by IL-1b. Considering the crucial role of IL-1b in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1b mediates the loss of anti-inflammatory T H 17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. Methods: To assess proinflammatory versus anti-inflammatory T H 17 cell functions, we performed suppression assays and tested the effects of IL-1b dependent and independent T H 17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in T H 17 cell functions before and during therapy with IL-1b-blocking drugs. Results: Both T H 17 cell subsets differ in their ability to suppress T-cell proliferation and their ability to modulate proinflammatory cytokine production by antigen-presenting cells because of their differential IL-10 expression properties. In patients with Schnitzler syndrome, systemic overproduction of IL-1b translates into a profound loss of anti-inflammatory T H 17 cell functionalities, which can be reversed by anti-IL-1b treatment. Conclusion: IL-1b signaling determines the differential expression pattern of IL-10, which is necessary and sufficient to induce proinflammatory versus anti-inflammatory T H 17 cell functions. Our data introduce T H 17 cell subsets as novel players in autoinflammation and thus novel therapeutic targets in