The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-α
The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-α
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DOI：
10.1042/bj20040099
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发表时间：
2004-06-15
影响因子：
4.1
通讯作者：
Recklies, AD
中科院分区：
文献类型：
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作者：
Ling, H;Recklies, AD
几丁质酶3样蛋白HC-gp39(人软骨糖蛋白39)的表达与基质周转增加和组织重塑有关。在炎症性和退行性关节炎患者的血清和滑液中发现了高水平的这种蛋白。为了探讨HC-gp39在炎性细胞因子诱导的基质降解中的作用，我们研究了HC-gp39对结缔组织细胞对肿瘤坏死因子-α和白介素1(IL-1)激活信号通路、产生基质金属蛋白酶和趋化因子的影响。人皮肤成纤维细胞或关节软骨细胞在有HC-gp39存在的情况下，用IL-1或TNF-α刺激后，p38丝裂原活化蛋白激酶和应激活化蛋白激酶/Jun氨基末端激酶的磷酸化均显著降低，而核因子kappaB的核转位则不受阻碍。HC-gp39抑制细胞因子诱导的MMPI、MMP3和MMP13的分泌，以及趋化因子IL-8的分泌。HC-gp39的抑制作用依赖于磷酸化肌动蛋白3-激酶的活性，而HC-gp39处理细胞后导致AKT介导的丝氨酸/苏氨酸磷酸化的凋亡信号调节激酶1，这一过程可能是HC-gp39下调细胞因子信号通路的原因之一。这些结果表明，HC-gp39在限制炎性细胞因子的分解代谢效应方面具有生理作用。
Expression of the chitinase 3-like protein HC-gp39 (human cartilage glycoprotein 39) is associated with conditions of increased matrix turnover and tissue remodelling. High levels of this protein have been found in sera and synovial fluids of patients with inflammatory and degenerative arthritis. In order to assess the role of HC-gp39 in matrix degradation induced by inflammatory cytokines, we have examined its effect on the responses of connective tissue cells to TNF-alpha (tumour necrosis factor-alpha) and IL-1 (interleukin-1) with respect to activation of signalling pathways and production of MVPs (matrix metalloproteases) and chemokines. Stimulation of human skin fibroblasts or articular chondrocytes with IL-1 or TNF-alpha in the presence of HC-gp39 resulted in a marked reduction of both p38 mitogen-activated protein kinase and stress-activated protein kinase/Jun N-terminal kinase phosphorylation, whereas nuclear translocation of nuclear factor kappaB proceeded unimpeded. HC-gp39 suppressed the cytokine-induced secretion of MMPI, MMP3 and MMP13, as well as secretion of the chemokine IL-8. The suppressive effects of HC-gp39 were dependent on phosphomositicle 3-kinase activity, and treatment of cells with HC-gp39 resulted in AKT-mediated serine/threonine phosphorylation of apoptosis signal-regulating kinase 1. This process could therefore be responsible for the down-regulation of cytokine signalling by HC-gp39. These results suggest a physiological role for HC-gp39 in limiting the catabolic effects of inflammatory cytokines.