IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis.
IL-22 is an IFN-IL-10 cytokine family member, which is produced by activated Th1 and NK cells and acts primarily on epithelial cells. Here we demonstrate that IL-22, in contrast to its relative IFN-gamma, regulates the expression of only a few genes in keratinocytes. This is due to varied signal transduction. Gene expressions regulated by IL-22 should enhance antimicrobial defense [psoriasin (S100A7), calgranulin A (S100A8), calgranulin B (S100A9)], inhibit cellular differentiation (e.g., profilaggrin, keratins 1 and 10, kallikrein 7), and increase cellular mobility [e.g., matrix metalloproteinease 1 (MMP1, collagenase 1), MMP3 (stromelysin 1), desmocollin 1]. In contrast, IFN-gamma favored the expression of MHC pathway molecules, adhesion molecules, cytokines, chemokines, and their receptors. The IL-22 effects were transcriptional and either independent of protein synthesis and secretion, or mediated by a secreted protein. Inflammatory conditions, but not keratinocyte differentiation, amplified the IL-22 effects. IL-22 application in mice enhanced cutaneous S100A9 and MMP1 expression. High IL-22 levels in psoriatic skin were associated with strongly up-regulated cutaneous S100A7, S100A8, S100A9, and MMP1 expression. Psoriatic patients showed strongly elevated IL-22 plasma levels, which correlated with the disease severity. Expression of IL-22 and IL-22-regulated genes was reduced by anti-psoriatic therapy. In summary, despite similarities, IFN-gamma primarily amplifies inflammation, while IL-22 may be important in the innate immunity and reorganization of epithelia.
Wolk
Kerstin
K
Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, University Hospital Charité, Berlin, Germany.
Witte
Ellen
E
Wallace
Elizabeth
E
Döcke
Wolf-Dietrich
WD
Kunz
Stefanie
S
Asadullah
Khusru
K
Volk
Hans-Dieter
HD
Sterry
Wolfram
W
Sabat
Robert
R
D000818:Animals; D040501:Calgranulin A / Q000235:genetics; D040502:Calgranulin B / Q000235:genetics; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D011565:Psoriasis / Q000209:etiology*; D000097043:Interleukin-22
D040501:Calgranulin A; D040502:Calgranulin B; D007371:Interferon-gamma; D007378:Interleukins; D020781:Matrix Metalloproteinase 1; D000097043:Interleukin-22