ABSTRACT
OBJECTIVE AND DESIGN: The effects of the anticytokine interleukin 10 (IL-10) are mediated by specific receptors. In this study we examined the role of the IL-10 receptor (IL-10R) in the pathophysiology of atopic eczema. MATERIALS AND METHODS: For this purpose we analyzed the expression of IL-10R in the skin of patients with acute and chronic atopic eczema in comparison to the expression in healthy individuals using in situ binding experiments with fluorescently labeled IL-10 and semiquantitative reverse transcriptase-PCR specific for IL-10R1. In addition, we studied the influence of the Th2-associated cytokine interleukin-4 (IL-4), the Th1-associated gamma-interferon (IFN-gamma), the immunosuppressive drug FK506, the H1-antagonist loratadine and UVA irradiation on the expression of IL-10R1 in cultured normal human keratinocytes. RESULTS: We found that IL-10 receptor mRNA and protein are strongly downregulated in acute phase atopic lesions. Furthermore we could show that IL-4, IFN-gamma, FK506, loratadine and UVA enhance the mRNA levels of the IL-10R1 in vitro in normal cultured keratinocytes. We could also demonstrate restored IL-10R1 mRNA levels in lesional atopic skin of a patient after UVA1 therapy. CONCLUSIONS: Our results demonstrate for the first time that IL-10 receptors may have a role in the pathogenesis of atopic eczema and its upregulation by FK506 and UVA could explain the therapeutic efficacy of these agents.
Subject(s)
Dermatitis, Atopic/genetics , Dermatitis, Atopic/physiopathology , Keratinocytes/drug effects , Receptors, Interleukin/genetics , Acute Disease , Adult , Aged , Cells, Cultured , Chronic Disease , Cytokines/genetics , Cytokines/pharmacology , Dermatitis, Atopic/radiotherapy , Gene Expression Regulation/drug effects , Gene Expression Regulation/radiation effects , Humans , Immunosuppressive Agents/pharmacology , Keratinocytes/radiation effects , Middle Aged , RNA, Messenger/drug effects , RNA, Messenger/metabolism , RNA, Messenger/radiation effects , Receptors, Interleukin/analysis , Receptors, Interleukin/drug effects , Receptors, Interleukin/radiation effects , Receptors, Interleukin-10 , Tacrolimus/pharmacology , Ultraviolet TherapyABSTRACT
Psoriasis is a common hyperproliferative and inflammatory skin disease with a prevalence of 0.5-3%. Lesional skin is characterized by pathological overexpression of proinflammatory cytokines such as IL-8 and its receptor and the decreased presence of negative regulatory control factors like the anti-oncogene p53. The expression of these genes can be modulated in the opposite direction by antipsoriatic drugs. Another possible candidate gene is the receptor for the anti-inflammatory cytokine IL-10 (IL-10R). Recently, vitamin D3 and its analogues have attracted interest as new therapeutic agents in the treatment of psoriasis. In extension of these findings we studied here the effect of the physiologically active metabolite, 1,25-dihydroxyvitamin D3 (calcitriol) and its synthetic analogue calcipotriol (MC 903) on the expression of the IL-10R in HaCaT cells by RT-PCR. IL-10 receptor gene expression was effectively induced in the range of 10(-8)-10(-9) M. Upregulation by calcitriol was about 10-fold, by calcipotriol 12-fold. Induction of the receptor for the anti-inflammatory cytokine IL-10 may be involved in the antipsoriatic action of vitamin D derivatives.
Subject(s)
Calcitriol/analogs & derivatives , Calcitriol/pharmacology , Gene Expression/drug effects , Keratinocytes/metabolism , Receptors, Interleukin/genetics , Cell Line , Dermatologic Agents/pharmacology , Humans , Polymerase Chain Reaction , RNA, Messenger/metabolism , RNA-Directed DNA Polymerase , Receptors, Interleukin-10ABSTRACT
The chronic skin disease psoriasis is characterized by epidermal hyperproliferation and inflammation. The exact etiology of the disease is still unknown. At the molecular level, overexpression of growth factors and proinflammatory cytokines such as IL-8 and the corresponding receptor has been described in psoriatic plaques. On the other hand, the loss of inhibitory control mechanisms is involved in the pathogenesis of the disease, as exemplified by the reduced mRNA levels for the cell cycle inhibitor p53 found in lesional skin. Here we extend these findings to a cytokine with negative regulatory functions, IL-10. Only under certain conditions are human keratinocytes able to synthesize IL-10. In skin, pathological overexpression of IL-10 was described om atopic dermatitis. IL-10 exerts its effects via a specific receptor (IL-10R). We show here for the first time the presence and functionality of IL-10R in epidermal cells and its dramatically decreased expression in acute exanthematic psoriatic epidermis by in vitro and in situ binding studies. These results were substantiated using semiquantitative reverse transcriptase-PCR, demonstrating decreased expression of the IL-10R gene in psoriatic skin, its down-modulation by the proinflammatory cytokine IL-8, and its pharmacological induction in cultured cells. Biological responsiveness of epidermal cells toward IL-10 could also be demonstrated by a reduction of the growth rate and inhibition of IFN-gamma-induced HLA-DR expression. Our results provide the first evidence for a role of the IL-10R gene in the homeostasis of the epidermis and substantiate the concept of a loss of negative regulatory peptides as a step in the eruption of psoriasis.
