TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques
TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques
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DOI：
10.4049/jimmunol.175.4.2721
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发表时间：
2005-08-15
影响因子：
4.4
通讯作者：
Krueger, JG
中科院分区：
文献类型：
--
作者：
Gottlieb, AB;Chamian, F;Krueger, JG
市售TNF阻断药物在病变组织中的作用机制仍不完全清楚。由于银屑病斑块可以重复活检，因此在10名银屑病患者中研究了用依那西普（可溶性TNFR）阻断TNF/α光敏素的效果，治疗6个月。组织学反应、炎症基因表达和细胞。评估银屑病斑块中的浸润。IL-1和IL-8（立即/早期基因）迅速完全减少，随后许多其他炎症相关基因逐渐减少，最后浸润性髓样细胞（CD 11 c（+）细胞）和T淋巴细胞减少较慢。观察到的IL-8、IFN-γ诱导蛋白-10（CXCL 10）和MIP-3 α（CCL 20）mRNA表达的降低可能分别导致中性粒细胞、T细胞和树突状细胞（DC）浸润的减少。DC可能在治疗中活化较少，如IL-23 mRNA和诱导型NO合酶mRNA和蛋白质降低所示。T细胞炎性基因表达（IFN-γ、STAT-1、颗粒酶B）和T细胞数量的减少可能是由于DC介导的T细胞活化减少。因此，依那西普诱导的TNF/淋巴毒素阻断可能会打破DC激活和成熟、随后的T细胞激活以及多种细胞类型（包括淋巴细胞、中性粒细胞、DC和角质形成细胞）产生细胞因子、生长因子和趋化因子的潜在自我维持循环。这导致银屑病斑块特征性的表皮增生和皮肤炎症逆转。
The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood. Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months. Histological response, inflammatory gene expression, and cellular. infiltration in psoriasis plaques were evaluated. There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c(+) cells) and T lymphocytes. The observed decreases in IL-8, IFN-gamma-inducible protein-10 (CXCL10), and MIP-3 alpha (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively. DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein. Decreases in T cell-inflammatory gene expression (IFN-gamma, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation. Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes. This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques.