IL-22 in tissue-protective therapy

Abstract

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.

Figure 1

Structure chart-like illustration of IL-22 signalling related to cytokine function. Regardless of whether endogenously produced in response to an epithelial insult or provided in the course of tissue-protective therapy, IL-22 will activate its heterodimeric IL-22R1/IL-10R2 receptor, which is predominantly expressed at the liver and host/environment interfaces. Subsequent to receptor activation, signal transduction mechanisms are engaged that are greatly dominated by STAT3 along with activation of MAPK and Akt pathways. This specific profile of cellular activation mediates proliferation and anti-apoptosis, finally increasing tissue robustness and stress resistance. Through these pathways, IL-22 is capable of mediating tissue protection in the context of various pathogenic conditions. However, a latent pro-inflammatory role of IL-22 related to activation of STAT1 and NF-κB may counteract the therapeutic potential of this cytokine in a context-specific manner. IL-10R2, IL-10 receptor chain-2; IL-22R1, IL-22 receptor chain-1.

Figure 2

Summary scheme and contraposition of the protective and pathogenic properties of IL-22, expressed in a range of conditions. IBD, inflammatory bowel disease; RA, rheumatoid arthritis; VILI, ventilator-induced lung injury.