Heme oxygenase-1 inhibits T cell-dependent skin inflammation and differentiation and function of antigen-presenting cells
Heme oxygenase-1 inhibits T cell-dependent skin inflammation and differentiation and function of antigen-presenting cells
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DOI：
10.1111/j.1600-0625.2007.00581.x
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发表时间：
2007-08-01
影响因子：
3.6
通讯作者：
Doecke, Wolf-Dietrich
中科院分区：
文献类型：
--
作者：
Listopad, Joanna;Asadullah, Khusru;Doecke, Wolf-Dietrich
血红素氧合酶-1(HO-1)在银屑病皮肤中升高。我们要求了解HO-1的生理和药理诱导对皮肤免疫的影响，以及HO-1诱导免疫调节的机制。我们发现，在银屑病和特应性湿疹中，皮肤HO-1的表达上调与细胞因子信号转导抑制因子(SOCS)1和SOCS3的表达相当，而在卵清蛋白诱导的晚期反应(LPR)和2，4-二硝基氟苯(DNFB)诱导的接触性超敏反应(CHS)中，HO-1的表达暂时增加。HO-1抑制可增强皮肤炎症，而HO-1诱导剂钴原卟啉(CoPP)治疗可消除皮肤炎症，无论是在致敏前后还是在激发前。抑制HO-1可特异性阻断COPP的抗炎作用。CoPP对小鼠脾细胞增殖和人混合白细胞反应及淋巴细胞转化试验均有抑制作用。CoPP诱导抗原提呈细胞HO-1表达，抑制单核细胞辅助分子表达，抑制单核细胞来源的树突状细胞(MDDC)的分化成熟。降低肿瘤坏死因子(TNF)-α和白介素12(IL-12)的产生，增加IL-10的分泌。CoPP处理和HO-1转导的MDDC的抗原提呈能力降低。我们首次证明了HO-1在限制皮肤炎症中的生理作用，并将药物诱导HO-1作为治疗T细胞依赖型炎症性皮肤病的一种方法。抑制抗原提呈细胞可能是HO-1的主要抗炎机制之一。
Heme oxygenase-1 (HO-1) is increased in psoriatic skin. We asked for the impact of physiological and pharmacological HO-1 induction on skin immunity and the mechanisms involved in HO-1-induced immunomodulation. We found cutaneous HO-1 expression upregulated comparable with suppressors of cytokine signalling (SOCS)1 and SOCS3 in psoriasis and atopic eczema and temporarily increased in murine ovalbumin-induced late phase reaction (LPR) and 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). Cutaneous inflammation was enhanced by HO-1 inhibition and was abrogated by treatment with the HO-1 inducer cobaltic protoporphyrin (CoPP) both when applied around sensitization or before challenge. HO-1 inhibition specifically prevented the anti-inflammatory CoPP effect. CoPP inhibited T cell proliferation in splenocytes of treated mice and in human mixed leukocyte reaction and lymphocyte transformation test. CoPP induced HO-1 in antigen-presenting cells and depressed monocytic accessory molecule expression and the differentiation and maturation of monocyte-derived dendritic cells (MDDC). It decreased tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 production while increasing IL-10 secretion. The antigen-presenting capacity was diminished in CoPP-treated and HO-1-transduced MDDC. We demonstrate for the first time the physiological role of HO-1 in the limitation of skin inflammation and implement pharmacological HO-1 induction as a therapeutic approach for T cell-dependent inflammatory dermatoses. Suppression of antigen-presenting cells may represent a main anti-inflammatory mechanism of HO-1.