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.

Up-Regulated Expression of the CXCR2 Ligand KC/GRO-α in Atherosclerotic Lesions Plays a Central Role in Macrophage Accumulation and Lesion Progression

“…In this regard, CXCR2 expression is highly regulated by cytokines such as IL-4, IL-10, and IL-13 and by other factors that may regulate vascular inflammation in vivo. [35][36][37][38] In the intermediate atherosclerosis stage, macrophages in the lesions of the CXCR2 Ϫ/Ϫ BMT mice were located more superficially on the lumenal side of the intima rather than dispersed throughout the intima as in the CXCR2 ϩ/ϩ BMT mice. Moreover, in the advanced stages of atherosclerosis, the lesions of the CXCR2 Ϫ/Ϫ BMT mice demonstrated little progression beyond the intermediate stage with a relatively marked decline in lesion macrophage staining.…”

IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity

“…These clinical trials were performed before a detailed understanding of the molecular mechanism of IL-10's anti-inflammatory function was established and it was therefore difficult to optimize the treatment. Disease-associated proinflammatory cytokines such as TNF-a, IL-1b, IL-12, and IL-17 were reduced by half in some studies, indicating a pharmacodynamic activity (43). However, the suppression of IL-1 and TNF-a lasted only as long as the serum concentration of IL-10 was sufficiently elevated, returning to high values 24 hours after the IL-10 injection (44).…”

Distribution of CXCR2 +1208 T/C gene polymorphisms in relation to opportunistic infections among HIV-infected patients in Limpopo Province, South Africa

“…CXCR2 and its chemokine ligands genotypes are involved in a wide range of acute and chronic inflammatory diseases, including acute respiratory distress syndrome (Kurdowska et al, 2002), rheumatoid arthritis (Erdem et al, 2005;Lally et al, 2005), psoriasis (Reich et al, 2001), inflammatory bowel disease (Banks et al, 2003), chronic obstructive pulmonary disease and asthma (Keatings et al, 1996;Beeh et al, 2003;Chapman et al, 2009), aggressive cancer (Snoussi et al, 2010), cystic fibrosis (Koller et al, 1997), and atherosclerosis (Bizzarri et al, 2006). However, whether different genotypes of the genes coding for these cytokines are involved in the susceptibility to opportunistic infections among HIV patients is not clear.…”