Influence of LPS, TNF, TGF-�1 and IL-4 on the expression of MMPs, TIMPs and selected cytokines in rat synovial membranes incubated in vitro

Abstract

Abstract. Synovial membranes are formed by four main types of cells, i.e. fibroblasts, macrophages, epitheliocytes and adipocytes. To study the combined effect of various factors on these cell populations, synovial membranes dissected from rat knee joints were incubated in control medium or medium with lipopolysaccharide (LPS), TNF, TGF-ß1 or IL-4 for 12 h. LPS stimulated TNF secretion and both agents stimulated secretion of IL-6. TGF-ß1 slightly increased IL-6 secretion. LPS increased the mRNA levels of IL-6, IL-1ß, TGF-ß1, MMP1a, MMP1b, MMP3, MMP9, MMP13, MMP14, TIMP1 and TIMP3 while the mRNA levels of MMP2, TIMP2 and TIMP4 were significantly decreased. Expression of IL-1ß, MMP1a, MMP1b, MMP3, MMP9, MMP13 and TIMP1 increased after TNF treatment, while mRNA levels of MMP2, MMP14, TIMP2, TIMP3 and TIMP4 were decreased. TGF-ß1 decreased the mRNA levels of IL-1ß, all MMPs, TIMP1, TIMP2, TIMP4 and increased mRNA levels of itself and TIMP3. IL-4 decreased mRNA levels of IL-1ß, TGF-ß1, MMP2, MMP9, MMP13 and all TIMPs. Only LPS decreased the amount and activity of MMP2. The effect of LPS and cytokines on most of the MMPs and TIMPs produced by whole synovial membrane was in good agreement with previous studies on their action on similar types of cells as those present in synovial membranes, but originating from other tissues. All tested agents decreased MMP2 mRNA expression levels and in the case of LPS also the protein level and its activity determined by zymography, contrary to previous observations on isolated cell populations. This indicates that the response of the organized tissue is an interplay of all components and cannot be deduced from the individual reactions.

Cyclical strain modulates metalloprotease and matrix gene expression in human tenocytes via activation of TGFβ

“…Some of the gene changes in response to TGFβ have previously been reported in other cell types. For example TGFβ is reported to regulate ADAM12 [54], ADAMTS1 [55], ADAMTS4 [56,57], ADAMTS16 [58], TIMP3 [59], TIMP4 [60], thrombospondin [61], aggrecan [62], collagen and fibronectin [63]. These responses are analogous to those seen in our model with TGFβ and strain, further supporting our conclusion that TGFβ plays a key role in the strain regulation of most metalloproteinase genes.…”

LPS Counter Regulates RNA Expression of Extracellular Proteases and Their Inhibitors in Murine Macrophages

“…In addition, our expression data is corroborated by studies of LPS-treated human-derived monocytes, in which increased levels of MMP9, MMP10, MMP14, and decreased levels of TIMP-2 were reported [15]. LPS treatment of isolated tissues, containing a mixed cell population including macrophages, also leads to increased MMP and decreased TIMP2 RNA expression levels [18]. Interestingly, the latter study also reported altered expression of genes that were not affected by LPS treatment of RAW 264.7 cells in the current study.…”

Lipopolysaccharide Induces Pro-Inflammatory Cytokines and MMP Production via TLR4 in Nasal Polyp-Derived Fibroblast and Organ Culture

“…Previous studies have shown that inflammatory cytokines induce MMPs, which may be a pivotal role for inflammatory cytokines such as IL-6 and IL-8 in the pathogenesis of diseases such as rheumatoid arthritis [25], chronic obstructive pulmonary disease [26], and corneal ulceration [27]. We showed that IL-6, IL-8 and MMP-1were produced by LPS in nasal polyp-derived fibroblasts.…”