Background:The transcription factor T-bet is pivotal for initiation of Th1-related immunoactivation. Identification of novel genes directly regulated by T-bet is crucial. Results: Genome-wide analysis and subsequent experiments revealed that T-bet up-regulates IL-36␥/IL-1F9 in myeloid cells. Conclusion: IL-1-related IL-36␥ is a direct T-bet target in myeloid cells. Significance: Observations suggest that IL-36␥, besides IFN␥, contributes to T-bet functions in immunopathology.

IL‐22, a member of the IL‐10 cytokine family, has recently gained significant attention as a protective agent in murine models of diseases driven by epithelial injury. Like its biochemical and functional sibling IL‐10, IL‐22 elicits cellular activation primarily by engaging the STAT3 signalling pathway. Exclusively produced by leukocytes, but targeting mostly cells of epithelial origin, IL‐22 has been proposed as a specialized cytokine messenger acting between leukocytic and non‐leukocytic cell compartments. A lack of response in leukocytes to IL‐22 mirrors tightly controlled IL‐22 receptor expression and probably explains the apparent lack of instant adverse effects after systemic IL‐22 administration to mice. Anti‐apoptotic, pro‐proliferative and pro‐regenerative characteristics the major biological properties of this cytokine. Specifically, application of IL‐22 is associated with tissue protection and/or regeneration in murine models of infection/microbe‐driven inflammation at host/environment interfaces, ventilator‐induced lung injury, pancreatitis and liver damage. Overall, preclinical studies would support therapeutic administration of seemingly well‐tolerated recombinant IL‐22 for treatment of an array of acute diseases manifested in epithelial tissues. However, the feasibility of prolonged administration of this cytokine is expected to be restricted by the tumourigenic potential of the IL‐22/STAT3 axis. IL‐22, moreover, apparently displays an inherent context‐specific capacity to amplify distinct aspects of autoimmune inflammation. Here, the prospects, expectations and restrictions of IL‐22 administration in tissue‐protective therapy are discussed.

Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol.

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Overdosing of the analgesic acetaminophen (APAP, paracetamol) is a major cause of acute liver injury. Whereas toxicity is initiated by hepatocyte necrosis, course of disease is regulated by mechanisms of innate immunity having the potential to serve in complex manner pathogenic or pro-regenerative functions. Interleukin (IL)-36γ has been identified as novel IL-1-like cytokine produced by and targeting epithelial (-like) tissues. Herein, we investigated IL-36γ in acute liver disease focusing on murine APAP-induced hepatotoxicity. Enhanced expression of hepatic IL-36γ and its prime downstream chemokine target CCL20 was detected upon liver injury. CCL20 expression coincided with the later regeneration phase of intoxication. Primary murine hepatocytes and human Huh7 hepatocellular carcinoma cells indeed displayed enhanced IL-36γ expression when exposed to inflammatory cytokines. Administration of IL-36 receptor antagonist (IL-36Ra) decreased hepatic CCL20 in APAP-treated mice. Unexpectedly, IL-36Ra likewise increased late phase hepatic injury as detected by augmented serum alanine aminotransferase activity and histological necrosis which suggests disturbed tissue recovery upon IL-36 blockage. Finally, we demonstrate induction of IL-36γ in inflamed livers of endotoxemic mice. Observations presented introduce IL-36γ as novel parameter in acute liver injury which may contribute to the decision between unleashed tissue damage and initiation of liver regeneration during late APAP toxicity.