The Journal of immunology : official journal of the American Association of Immunologists
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It has been previously reported that dietary fish oils, which are rich in the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, can exert beneficial effects in inflammatory bowel disease. In this study, we investigated the effects of docosahexaenoic acid-derived lipid mediator maresin 1 (MaR1) in dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice. Systemic treatment with MaR1 significantly attenuated both DSS- and 2,4,6-trinitrobenzene sulfonic acid-induced colonic inflammation by improving the disease activity index and reducing body weight loss and colonic tissue damage. ⋯ Moreover, incubation of LPS-stimulated bone marrow-derived macrophage cultures with MaR1 reduced neutrophil migration and reactive oxygen species production, besides decreasing IL-1β, TNF-α, IL-6, and INF-γ production. Interestingly, macrophages incubated only with MaR1 showed a significant upregulation of mannose receptor C, type 1 mRNA expression, an M2 macrophage phenotype marker. These results indicate that MaR1 consistently protects mice against different models of experimental colitis, possibly by inhibiting the NF-κB pathway and consequently multiple inflammatory mediators, as well as by enhancing the macrophage M2 phenotype.
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The JAKs receive continued interest as therapeutic targets for autoimmune, inflammatory, and oncological diseases. JAKs play critical roles in the development and biology of the hematopoietic system, as evidenced by mouse and human genetics. JAK1 is critical for the signal transduction of many type I and type II inflammatory cytokine receptors. ⋯ Paw swelling, bone and cartilage degradation, and levels of inflammatory cytokines were reduced by GLPG0634 treatment. Efficacy of GLPG0634 in the collagen-induced arthritis models was comparable to the results obtained with etanercept. In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases.
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Mast cells are characterized by an abundance of secretory granules densely packed with inflammatory mediators such as bioactive amines, cytokines, serglycin proteoglycans with negatively charged glycosaminoglycan side chains of either heparin or chondroitin sulfate type, and large amounts of positively charged proteases. Despite the large biological impact of mast cell granules and their contents on various pathologies, the mechanisms that regulate granule composition are incompletely understood. In this study, we hypothesized that granule composition is dependent on a dynamic electrostatic interrelationship between different granule compounds. ⋯ In contrast, mast cells with combined protease deficiency displayed a profound distortion of granule integrity, as seen both by conventional morphological criteria and by transmission electron microscopy. An assessment of granule content revealed that the distorted granule integrity in multiprotease-deficient mast cells was associated with a profound reduction of highly negatively charged heparin, whereas no reduction in chondroitin sulfate storage was observed. Taken together with previous findings showing that the storage of basic proteases conversely is regulated by anionic proteoglycans, these data suggest that secretory granule composition in mast cells is dependent on a dynamic interrelationship between granule compounds of opposite electrical charge.