Background: Anorexia, body wasting, inflammation, muscle, and adipose tissue loss are hallmarks of cancer cachexia, a syndrome that affects the majority of cancer patients, impairing their ability to endure chemotherapeutic therapies and reducing their lifespan. In the last 10 years, alterations of protein turnover and impairment of adult myogenesis have been proposed as major contributing factors.Methods: Muscle stem cells, including satellite cells, mesoangioblasts, and fibroadipogenic progenitors, were isolated and characterized from C26 colon carcinoma‐bearing (C26) mice. Circulating levels of interleukin‐4/13 (IL4/IL13) were analysed by ELISA, and the effects of IL4 on muscle mass and function, protein synthesis, muscle regeneration, and myogenic progenitor cell number were analysed at both functional (treadmill and grip test) and molecular levels (qRT–PCR, immunofluorescence analysis, surface sensing of translation, and western blot). The Kaplan–Meier test was used to analyse the survival curve of IL4‐treated and IL4‐untreated C26 mice.Results: The administration of IL4 to C26 mice rescued muscle mass by increasing protein synthesis. The IL4 treatment improved performances and prolonged survival of C26 mice. IL4 administration re‐established both number and function of satellite cells and fibroadipogenic progenitors without affecting mesoangioblasts in C26 mice, rescuing myogenesis. Upon IL4 treatment, a high number of cytotoxic lymphocytes and type II macrophages were observed with a subsequent increase in necrotic areas of C26 tumours.Conclusions: The results here presented shed new light on IL4 signalling during muscle wasting and early stages of muscle regeneration that explain the beneficial effect observed in IL4‐treated C26 mice. These findings might aid to develop therapeutic approaches to improve mobility and quality of life in cachectic patients.

Via the histamine H₄‐receptor (H₄R), histamine promotes the pathogenesis of experimental allergic asthma in mice. Application of H₄R antagonists during sensitization as well as during provocation reduces the severity of the disease. However, the specific cell types functionally expressing H₄R in experimental allergic asthma have not been well characterized in vivo. In this study, we identified the cell type(s) responsible for H₄R activity in experimental asthma and related physiological mechanisms. Using H₄R‐deficient mice, we studied the role of H₄R in the sensitization and effector phase. DCs lacking H₄R expression during the in vitro sensitization reaction resulted in effector T cells unable to induce an entire eosinophilic inflammation in the lung upon adoptive transfer in vivo. Recipient mice lacking H₄R expression, which were adoptively transferred with H₄R^+/+T cells polarized in the presence of H₄R^+/+DCs, showed reduced signs of inflammation and ameliorated lung function. Here, we provide in vivo evidence that in experimental asthma in mice the H₄R specifically regulates activation of DCs during sensitization, while in the effector phase the H₄R is active in cells involved in the activation of eosinophils, and possibly other cells. A putative therapy targeting the H₄R may be an option for asthma patients developing IL‐5‐dependent eosinophilia.

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H₁R) antagonists, which are used to control allergic inflammation, antagonists at H₂R, which therapeutically decrease gastric acid release, and an antagonist at H₃R, which is indicated to treat narcolepsy. Ligands at H₄R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H₄R ligands so far. Nevertheless, pre-clinically, H₄R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H₁R, H₂R, and H₃R do not provide an effect on inflammation, supporting the idea that H₄R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H₄R in inflammatory and inflammation-associated diseases of the gut.