title: Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin-8/CXCR2 pathway and normalization of keratinocyte maturation.
abstract: Psoriasis is a chronic inflammatory skin disease in which epidermal hyperplasia results from the release of cytokines by infiltrating type 1 T cells. Up- regulation of endogenous interleukin-10 controls type 1 skin responses in animal models; however, interleukin-10 production is low in psoriatic lesions. Consistent with an important role of interleukin-10 in psoriasis, we and colleagues have recently demonstrated clinical efficacy of subcutaneous administration of recombinant interleukin-10 to affected patients. Here, we studied the effects of interleukin-10 on disease-related inflammatory pathways. Patients were treated with recombinant interleukin-10 over 6 wk in an open-label phase II clinical trial. Tissue was obtained before and after therapy and examined by histology/immunohistochemistry, in situ hybridization, and quantitative real-time reverse transcription-polymerase chain reaction. Ten of 14 patients showed a marked reduction of the clinical disease activity. The clinical response was associated with a significant decrease of cutaneous T cell infiltration and the lesional expression of type 1 cytokines interferon-gamma and tumor necrosis factor-alpha. Interleukin-10 inhibited the epidermal interleukin-8 pathway by downregulating the expression of interleukin-8, its receptor CXCR2, and its inducer interleukin-17, and partially reversed the aberrant keratinocyte maturation defining psoriatic epidermal pathology. Remarkably, there was evidence that genetic factors are involved in the response to interleukin-10 as individual variations in the downregulation of tumor necrosis factor-alpha were related to the presence of polymorphisms in the tumor necrosis factor-alpha promoter. These data suggest that excessive production of type 1 cytokines in human skin disease can be counter-regulated by the administration of recombinant interleukin-10. Genotypic analysis may help to identify patients that will preferentially respond to interleukin-10 therapy.
authors.affiliation: Department of Dermatology, Georg-August-University, Von-Siebold-Strasse 3, 37075 Göttingen, Germany. kreich@gwdg.ge
authors.forename: K
authors.initials: K
authors.lastname: Reich
authors.forename: C
authors.initials: C
authors.lastname: Garbe
authors.forename: V
authors.initials: V
authors.lastname: Blaschke
authors.forename: C
authors.initials: C
authors.lastname: Maurer
authors.forename: P
authors.initials: P
authors.lastname: Middel
authors.forename: G
authors.initials: G
authors.lastname: Westphal
authors.forename: U
authors.initials: U
authors.lastname: Lippert
authors.forename: C
authors.initials: C
authors.lastname: Neumann
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D003872:Dermatitis / Q000517:prevention & control*; D015536:Down-Regulation; D004817:Epidermis / Q000737:chemistry*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000627:therapeutic use*; D016209:Interleukin-8 / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology*; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011565:Psoriasis / Q000188:drug therapy*; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D016209:Interleukin-8; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10