Interleukin-31 (IL-31) is a type 2 helper T-cell-derived cytokine that has recently been shown to cause severe inflammation and tissue remodeling in multiple chronic diseases of the skin and lungs. IL-31 is upregulated in allergic and inflammatory diseases, including atopic dermatitis, asthma, cutaneous T-cell lymphomas, and allergic rhinitis, as well as autoimmune diseases such as systemic erythematosus. Overexpression of IL-31 in T cells causes severe inflammation, with histological features similar to skin lesions of patients with atopic dermatitis. However, the molecular mechanisms involved in IL31-driven pathological remodeling in skin diseases remain largely unknown. Here, we studied the role of IL-31 in skin damage as a result of intradermal administration of recombinant IL-31 into mice. Notably, IL-31 was sufficient to increase epidermal basal-cell proliferation and thickening of the epidermal skin layer. Our findings demonstrate a progressive increase in transepidermal water loss with chronic administration of IL-31 into the skin. Further, analysis of the skin transcriptome indicates a significant increase in the transcripts involved in epidermal-cell proliferation, epidermal thickening, and mechanical integrity. In summary, our findings demonstrate an important role for IL-31 signaling in epidermal cell proliferation and thickening that together may lead to impaired skin-barrier function in pathological remodeling of the skin.

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We describe a series of 18 cases of abdominal cocoon in patients presenting with features of small intestinal obstruction or perforative peritonitis, nine of whom had tubercular aetiology while the rest were idiopathic. Manifestations of abdominal tuberculosis such as mesenteric abscesses, enlarged and caseating mesenteric lymph nodes, and tubercles over the bowel serosa were found in only 55% patients who were ultimately diagnosed to have Tubercular aetiology. We conclude that a high index of suspicion for this rare cause of a common surgical emergency is desirable.

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Background: IL-31RA is a novel Type I cytokine receptor that pairs with oncostatin M receptor to mediate IL-31 signaling. Results: Th2 cytokines up-regulate IL-31RA signaling in macrophages. Conclusion: We demonstrate that the Th2 cytokines IL-4 and IL-13 were capable of up-regulating IL-31RA expression on macrophages. Significance: This newly identified counter-regulatory role between Th2 cytokine and the IL-31 signaling cascade may provide valuable insights into the pathobiology of allergic diseases.

IL-4 and IL-13 are major T-helper cell (Th) 2 cytokines implicated in the pathogenesis of several lung diseases, including pulmonary fibrosis. In this study, using a novel repetitive intradermal bleomycin model in which mice develop extensive lung fibrosis and a progressive decline in lung function compared with saline-treated control mice, we investigated profibrotic functions of Th2 cytokines. To determine the role of IL-13 signaling in the pathogenesis of bleomycin-induced pulmonary fibrosis, wild-type, IL-13, and IL-4Rα-deficient mice were treated with bleomycin, and lungs were assessed for changes in lung function and pulmonary fibrosis. Histological staining and lung function measurements demonstrated that collagen deposition and lung function decline were attenuated in mice deficient in either IL-13 or IL-4Rα-driven signaling compared with wild-type mice treated with bleomycin. Furthermore, our results demonstrated that IL-13 and IL-4Rα-driven signaling are involved in excessive migration of macrophages and fibroblasts. Notably, our findings demonstrated that IL-13-driven migration involves increased phospho-focal adhesion kinase signaling and F-actin polymerization. Importantly, in vivo findings demonstrated that IL-13 augments matrix metalloproteinase (MMP)-2 and MMP9 activity that has also been shown to increase migration and invasiveness of fibroblasts in the lungs during bleomycin-induced pulmonary fibrosis. Together, our findings demonstrate a pathogenic role for Th2-cytokine signaling that includes excessive migration and protease activity involved in severe fibrotic lung disease.

Th1 cells have different capacities to develop into memory cells based on their production of IFN-γ. In this study, the mechanism by which a homogenous population of IFN-γ-producing CD4 T cells was eliminated in vivo was assessed. When such cells were transferred into naive mice and activated with Ag, a striking decrease in the frequency of cells in the spleen and lung was observed. However, administration of neutralizing anti-IFN-γ Ab at the time of Ag challenge largely prevented the elimination of such cells. To determine whether IFN-γ was mediating its effects directly and/or indirectly, the ability of IFN-γ to effectively signal in such cells was assessed in vitro. Indeed, there was reduced phosphorylation of STAT1 in response to IFN-γ as well as markedly reduced expression of the IFN-γR β-chain. Furthermore, transfer of such cells into IFN-γR-deficient mice limited their death following activation with Ag. Together, these data suggest that IFN-γ acts in a paracrine manner to mediate the death of activated IFN-γ-producing Th1 cells. In contrast to Ag stimulation, administration of CpG alone resulted in the elimination of Th1 cells in IFN-γR−/− mice. These results show that in response to Ag stimulation, the death of IFN-γ-producing effector Th1 cells is controlled in an IFN-γ-dependent manner, whereas in response to innate activation, the death of IFN-γ-producing Th1 cells can occur through an IFN-γ-independent pathway. Collectively, these data show the multiple mechanisms by which Th1 effector cells are efficiently eliminated in vivo.

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