IL-22 Inhibits Epidermal Differentiation and Induces Proinflammatory Gene Expression and Migration of Human Keratinocytes

Abstract

IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22 has proinflammatory activities. IL-22 signals through a class II cytokine receptor composed of an IL-22-binding chain, IL-22RA1, and the IL-10RB subunit, which is shared with the IL-10R. In the present study, we show that short-term cultured human epidermal keratinocytes express a functional IL-22R but no IL-10R. Accordingly, IL-22 but not IL-10 induces STAT3 activation in keratinocytes. Using a cDNA array screening approach, real-time RT-PCR, and Western blot analysis, we demonstrate that IL-22 up-regulates, in a dose-dependent manner, the expression of S100A7, S100A8, S100A9, a group of proinflammatory molecules belonging to the S100 family of calcium-binding proteins, as well as the matrix metalloproteinase 3, the platelet-derived growth factor A, and the CXCL5 chemokine. In addition, IL-22 induces keratinocyte migration in an in vitro injury model and down-regulates the expression of at least seven genes associated with keratinocyte differentiation. Finally, we show that IL-22 strongly induces hyperplasia of reconstituted human epidermis. Taken together, these results suggest that IL-22 plays an important role in skin inflammatory processes and wound healing.

Pathophysiology of psoriasis: Recent advances on IL-23 and Th17 cytokines

“…However, IL-22R1 is not expressed on any immune cells and therefore has no direct effect on their activity [47]. Signaling through the IL-22 receptor in keratinocytes occurs through activation and phosphorylation of Stat3 [47,48].…”

Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma

“…Although IL-10 is immunosuppressive in the immune system, IL-20 subfamily cytokines are likely to be proinflammatory. 2,5,6 In monocytes IL-19 secretion in response to LPS and GM-CSF has been shown to induce monocyte production of proinflammatory cytokines. 7 IL-19 expression is also upregulated in psoriatic lesions, [8][9][10] in sera from asthmatic patients, and in the urine of uremic patients, although the source of IL-19 production has not yet been identified.…”

Association analysis of IL20RA and IL20RB genes in psoriasis

“…2,5 Both in vitro and in vivo, IL-20 promotes hyperproliferation and abnormal differentiation of keratinocytes that are characteristic features of psoriasis. 2,12,13 has been shown to induce expression of keratinocyte growth factor, which acts as a potent mitogen for human keratinocytes. 14 and is considered to contribute to the epidermal hyperplasia in psoriasis.…”

“…IL-20RB associates with IL-20RA to form IL-20RI that binds IL-19, IL20 and IL-24, and IL-20RB associates with IL-22RA1 to form IL-20-RII that binds IL-20 and IL-24. 2,13,[19][20][21] After binding of the different ligands to the receptor complexes, signals are predominantly transducted via Janus kinase-signal transducer and activation of transcription pathways. 22 IL-20-RI is mainly expressed in the skin, lung and reproductive organs as well as in various glands.…”

“…The expression of IL-20-RII seems to be more restricted with high levels detectable only in the skin. 2,13,[19][20][21] There are conflicting findings with regard to the expression of IL-20R subunits in skin lesions of psoriasis.…”