Acetaminophen-Induced Liver Injury Exposes Murine IL-22 as Sex-Related Gene Product

Abstract

Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.

Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis

“…2d ). This could be explained by IL-22ra1 being expressed more highly in females compared to males 20 . Impaired glycemic control is often characterized by a marked increase in peripheral insulin resistance 21 , 22 .…”

The Effect of Sex-Specific Differences on IL-10−/− Mouse Colitis Phenotype and Microbiota

“…Together with IL-17A, these two molecules regulate the body’s natural antimicrobial defenses to protect against enteric pathogens [ 28 ]. Although Gunasekera et al’s work was based only on IL-10 −/− male mice between 16 to 20 weeks of age, studies have reported a significantly enhanced production of IL-22 in the liver of females compared to male mice [ 29 ]. Interestingly, testosterone seems to regulate IL-22 production in the female liver [ 29 ], playing sex-dependent immunosuppressive effects [ 30 ].…”

“…Although Gunasekera et al’s work was based only on IL-10 −/− male mice between 16 to 20 weeks of age, studies have reported a significantly enhanced production of IL-22 in the liver of females compared to male mice [ 29 ]. Interestingly, testosterone seems to regulate IL-22 production in the female liver [ 29 ], playing sex-dependent immunosuppressive effects [ 30 ]. Estrogens, on another hand, have a complex role in inflammation and autoimmune disorders, with experimental evidence suggesting their involvement in gastrointestinal functions, potentially through estrogen receptor beta (ERβ).…”

Sex-Dependent Hepatoprotective Role of IL-22 Receptor Signaling in Non-Alcoholic Fatty Liver Disease-Related Fibrosis

“… 59 In addition, testosterone or dihydrotestosterone reduced IL22 production by female murine splenocytes after stimulation by either lipopolysaccharide or αCD3/CD28. 60 Moreover, in the imiquimod-induced psoriasis model, administration of estrogen agonists significantly modulated Th-derived IL22, thus aggravating psoriasis symptoms. 61 Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL22 expression in the context of NAFLD.…”