白细胞介素-1刺激的丝裂原活化蛋白激酶、活化蛋白-1（AP-1）和核因子κB（NF-κB）转录因子的抑制作用下调了关节软骨细胞中基质金属蛋白酶基因的表达。

Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes.

作者信息

Liacini Abdelhamid, Sylvester Judith, Li Wen Qing, Zafarullah Muhammad

机构信息

Département de Médecine and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame du CHUM, 1560 Sherbrooke est, Montreal, Québec, Canada H2L 4M1.

出版信息

Matrix Biol. 2002 Apr;21(3):251-62. doi: 10.1016/s0945-053x(02)00007-0.

DOI:10.1016/s0945-053x(02)00007-0

PMID:12009331

Abstract

Interleukin-1 (IL-1), the main cytokine instigator of cartilage degeneration in arthritis, induces matrix metalloproteinase-3 (MMP-3) and MMP-13 RNA and protein in chondrocytes. The molecular mechanisms of this induction were investigated with specific inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and activating protein (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors. IL-1 rapidly induced the activation of extracellular-signal regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK) MAPKs in the first-passage human femoral head OA chondrocytes. The ERK-MAPK pathway inhibitor, PD98059, attained 46-53% (MMP-3) and 59-66% (MMP-13) inhibition of RNA induction in human OA and 47-52% (MMP-3) and 69-73% (MMP-13) inhibition in bovine chondrocytes. U0126 conferred 37-77% (MMP-3) and 43-73% (MMP-13) suppression in human and 77-100% (MMP-3) and 96-100% (MMP-13) in bovine chondrocytes. P38 and JNK inhibitor, SB203580 caused 35-37% reduction of MMP-3 and MMP-13 RNA in human and 36-46% (MMP-3) and 60-88% (MMP-13) in bovine chondrocytes. Inhibitor of JNK, AP-1 and NF-kappa B, curcumin, achieved 48-99% suppression of MMP-3 and 45-97% of MMP-13 in human and 8-100% (MMP-3) and 32-100% (MMP-13) in bovine chondrocytes. NF-kappaB inhibitor, pyrrolidine dithiocarbamate yielded 83-84% reduction of MMP-3 and 38-55% for MMP-13 in human chondrocytes. In bovine chondrocytes, the induction decreased by 54-64% for MMP-3 and 74-93% for MMP-13 RNA. These results suggest the involvement of MAPKs, AP-1 and NF-kappa B transcription factors in the IL-1 induction of MMPs in chondrocytes. Inhibition of IL-1 signal transduction by these agents could be useful for reducing cartilage resorption by MMPs in arthritis.

摘要

白细胞介素-1（IL-1）是关节炎中软骨退变的主要细胞因子激发剂，可诱导软骨细胞中的基质金属蛋白酶-3（MMP-3）和MMP-13的RNA及蛋白质表达。通过丝裂原活化蛋白激酶（MAPK）信号通路、活化蛋白（AP-1）和核因子κB（NF-κB）转录因子的特异性抑制剂，研究了这种诱导的分子机制。IL-1可迅速诱导原代人股骨头骨关节炎软骨细胞中细胞外信号调节激酶（ERK）、p38蛋白和c-Jun氨基末端激酶（JNK）的MAPK激活。ERK-MAPK通路抑制剂PD98059对人骨关节炎中MMP-3 RNA诱导的抑制率达46 - 53%，对MMP-13 RNA诱导的抑制率达59 - 66%；对牛软骨细胞中MMP-3 RNA诱导的抑制率达47 - 52%，对MMP-13 RNA诱导的抑制率达69 - 73%。U0126对人软骨细胞中MMP-3的抑制率为37 - 77%，对MMP-13的抑制率为43 - 73%；对牛软骨细胞中MMP-3的抑制率为77 - 100%，对MMP-13的抑制率为96 - 100%。P38和JNK抑制剂SB203580可使人类软骨细胞中MMP-3和MMP-13 RNA减少35 - 37%，使牛软骨细胞中MMP-3减少36 - 46%，MMP-13减少60 - 88%。JNK、AP-1和NF-κB的抑制剂姜黄素，可使人类软骨细胞中MMP-3的抑制率达48 - 99%，MMP-13的抑制率达45 - 97%；使牛软骨细胞中MMP-3的抑制率达8 - 100%，MMP-13的抑制率达32 - 100%。NF-κB抑制剂吡咯烷二硫代氨基甲酸盐可使人类软骨细胞中MMP-3减少83 - 84%，MMP-13减少38 - 55%。在牛软骨细胞中，MMP-3 RNA诱导减少54 - 64%，MMP-13 RNA诱导减少74 - 93%。这些结果表明MAPKs、AP-1和NF-κB转录因子参与了IL-1诱导软骨细胞中MMPs的过程。这些药物对IL-1信号转导的抑制作用可能有助于减少关节炎中MMPs对软骨的吸收。