title: IL-21 promotes skin recruitment of CD4(+) cells and drives IFN-γ-dependent epidermal hyperplasia.
abstract: Psoriasis is a chronic inflammatory disorder of the skin characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. T cell-derived cytokines, such as IFN-γ and IL-17A, play a major role in the psoriasis-associated epidermal hyperplasia, even though factors/mechanisms that regulate the production of these cytokines are not fully understood. We have recently shown that IL-21 is synthesized in excess in psoriatic skin lesions and causes epidermal hyperplasia when injected intradermally in mice. Moreover, in the human psoriasis SCID mouse model, neutralization of IL-21 reduces both skin thickening and expression of inflammatory molecules, thus supporting the pathogenic role of IL-21 in psoriasis. However, the basic mechanism by which IL-21 promotes skin pathology remains unknown. In this study, we show that CD4(+) cells accumulate early in the dermis of IL-21-treated mice and mediate the development of epidermal hyperplasia. Indeed, IL-21 fails to induce skin damage in RAG1-deficient mice and CD4(+) cell-depleted wild-type mice. The majority of CD4(+) cells infiltrating the dermis of IL-21-treated mice express IFN-γ and, to a lesser extent, IL-17A. Studies in cytokine knockout mice show that IFN-γ, but not IL-17A, is necessary for IL-21-induced epidermal hyperplasia. Finally, we demonstrate that IFN-γ-producing CD4(+) cells infiltrating the human psoriatic plaque express IL-21R, and abrogation of IL-21 signals reduces IFN-γ expression in cultures of psoriatic CD4(+) cells. Data indicate that IL-21 induces an IFN-γ-dependent pathogenic response in vivo, thus contributing to elucidate a mechanism by which IL-21 sustains skin-damaging inflammation.
authors: Department of Internal Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors: Massimiliano
authors: M
authors: Sarra
authors: Roberta
authors: R
authors: Caruso
authors: Maria Laura
authors: ML
authors: Cupi
authors: Ivan
authors: I
authors: Monteleone
authors: Carmine
authors: C
authors: Stolfi
authors: Elena
authors: E
authors: Campione
authors: Laura
authors: L
authors: Diluvio
authors: Annamaria
authors: A
authors: Mazzotta
authors: Elisabetta
authors: E
authors: Botti
authors: Sergio
authors: S
authors: Chimenti
authors: Antonio
authors: A
authors: Costanzo
authors: Thomas T
authors: TT
authors: MacDonald
authors: Francesco
authors: F
authors: Pallone
authors: Giovanni
authors: G
authors: Monteleone
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D007371:Interferon-gamma; D000098546:Interleukin-21