The IL-1 family of cytokines encompasses eleven proteins that each share a similar β-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-1α (IL-1F1), IL-1β (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 α 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-1α and IL-33, for receptor-independent organ/tissue-specific regulation of inflammation is also reviewed.

Infections with the human pathogen Helicobacter pylori (H. pylori) can lead to severe gastric diseases ranging from chronic gastritis and ulceration to neoplastic changes in the stomach. Development and progress of H. pylori-associated disorders are determined by multifarious bacterial factors. Many of them interact directly with host cells or require specific receptors, while others enter the host cytoplasm to derail cellular functions. Several adhesins (e.g. BabA, SabA, AlpA/B, or OipA) establish close contact with the gastric epithelium as an important first step in persistent colonization. Soluble H. pylori factors (e.g. urease, VacA, or HtrA) have been suggested to alter cell survival and intercellular adhesions. Via a type IV secretion system (T4SS), H. pylori also translocates the effector cytotoxin-associated gene A (CagA) and peptidoglycan directly into the host cytoplasm, where cancer- and inflammation-associated signal transduction pathways can be deregulated. Through these manifold possibilities of interaction with host cells, H. pylori interferes with the complex signal transduction networks in its host and mediates a multi-step pathogenesis.

A cardinal feature of allergic disorders and immune responses is enhanced leukocyte trafficking. This is largely orchestrated by chemokines. The CC chemokine thymus‐ and activation‐regulated chemokine (TARC/CCL17) selectively attracts Th2 cells via the G protein‐coupled chemokine receptor CCR4. We show here that TARC/CCL17 is expressed by human T cells upon stimulation with IL‐4. Mapping of the transcriptional start site revealed the presence of two putative STAT6 binding motifs in proximity to the start position. EMSA and chromatin immunoprecipitation experiments demonstrated that STAT6 was able to bind to both motifs. A fragment of the TARC/CCL17 promoter containing both sites was tested in reporter gene assays for IL‐4 inducibility. The promoter was inducible in a STAT6‐deficient cell line only after introduction of functional STAT6. When mutations were inserted into one of the STAT6 motifs, IL‐4‐induced promoter activation was reduced. With both sites mutated, inducibility was completely abrogated. These data demonstrate collectively that T cells serve as a source of TARC/CCL17 when stimulated with IL‐4 and that STAT6 is essential for this.

Persistent infections with the human pathogen Helicobacter pylori (H. pylori) have been closely associated with the induction and progression of a wide range of gastric disorders, including acute and chronic gastritis, ulceration in the stomach and duodenum, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma. The pathogenesis of H. pylori is determined by a complicated network of manifold mechanisms of pathogen–host interactions, which involves a coordinated interplay of H. pylori pathogenicity and virulence factors with host cells. While these molecular and cellular mechanisms have been intensively investigated to date, the knowledge about outer membrane vesicles (OMVs) derived from H. pylori and their implication in bacterial pathogenesis is not well developed. In this review, we summarize the current knowledge on H. pylori-derived OMVs.

IL-31 is a T cell-derived cytokine that signals via a heterodimeric receptor composed of IL-31Rα and oncostatin M receptor β. 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. Because dendritic cells are the main activators of Th cell responses, we posed the question of whether dendritic cells express the IL-31R complex and govern immune responses triggered by IL-31. In the current study, we report that primary human CD1c⁺ as well as monocyte-derived dendritic cells significantly upregulate the IL-31Rα receptor chain upon stimulation with IFN-γ. EMSAs, chromatin immunoprecipitation assays, and small interfering RNA-based silencing assays revealed that STAT1 is the main transcription factor involved in IFN-γ–dependent IL-31Rα expression. Subsequent IL-31 stimulation resulted in a dose-dependent release of proinflammatory mediators, including TNF-α, IL-6, CXCL8, CCL2, CCL5, and CCL22. Because 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.

Dendritic cells (DCs) are key players in initiating and directing the immune response. Therefore, their activation state and functional differentiation need to be tightly controlled. The activating stimuli and their signaling networks have long been an area of focus in DC research. Recent investigations have also shed light on the mechanisms of counterregulation and fine-tuning of DC functions. One class of proteins involved in these processes is the family of suppressors of cytokine signaling (SOCS), whose members were originally described as feedback inhibitors of cytokine-induced JAK/STAT signaling. Essential roles in DC function have been assigned to SOCS1 and SOCS3. In this article, we show that SOCS2 also is involved in DC regulation. In human and in murine DCs, SOCS2 is a highly TLR-responsive gene, which is expressed in a time-delayed fashion beginning 8 h after TLR ligation. Functionally, silencing of SOCS2 in DCs results in hyperphosphorylation of STAT3 at later time points. As a consequence, SOCS2-deficient DCs secrete increased amounts of the cytokines IL-1β and IL-10, both being transcriptional targets of STAT3. We propose a model in which SOCS2 acts as a negative regulator of TLR-induced DC activation. The delayed expression of SOCS2 provides a mechanism of late-phase counterregulation and limitation of inflammation-driving DC activity.