Effects of C-reactive protein on the expression of matrix metalloproteinases and their inhibitors via Fcγ receptors on 3T3-L1 adipocytes

Abstract

The association between obesity and inflammation is well documented in epidemiological studies. Proteolysis of extracellular matrix (ECM) proteins is involved in adipose tissue enlargement, and matrix metalloproteinases (MMPs) collectively cleave all ECM proteins. Here, we examined the effects of C-reactive protein (CRP), an inflammatory biomarker, on the expression of MMPs and tissue inhibitors of metalloproteinases (TIMPs), which are natural inhibitors of MMPs, in adipocyte-differentiated 3T3-L1 cells. We analyzed the expression of Fcγ receptor (FcγR) IIb and FcγRIII, which are candidates for CRP receptors, and the effects of anti-CD16/CD32 antibodies, which can act as FcγRII and FcγRIII blockers on CRP-induced alteration of MMP and TIMP expression. Moreover, we examined the effects of CRP on the activation of mitogen-activated protein kinase (MAPK) signaling, which is involved in MMP and TIMP expression, in the presence or absence of anti-CD16/CD32 antibodies. Stimulation with CRP increased MMP-1, MMP-3, MMP-9, MMP-11, MMP-14, and TIMP-1 expression but did not affect MMP-2, TIMP-2, and TIMP-4 expression; TIMP-3 expression was not detected. Adipocyte-differentiated 3T3-L1cells expressed FcγRIIb and FcγRIII; this expression was upregulated on stimulation with CRP. Anti-CD16/CD32 antibodies inhibited CRP-induced expression of MMPs, except MMP-11, and TIMP-1. CRP induced the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK but did not affect SAPK/JNK phosphorylation, and Anti-CD16/CD32 attenuated the CRP-induced phosphorylation of p38 MAPK, but not that of ERK1/2. These results suggest that CRP facilitates ECM turnover in adipose tissue by increasing the production of multiple MMPs and TIMP-1 in adipocytes. Moreover, FcγRIIb and FcγRIII are involved in the CRP-induced expression of MMPs and TIMP-1 and the CRP-induced phosphorylation of p38, whereas the FcγR-independent pathway may regulate the CRP-induced MMP-11 expression and the CRP-induced ERK1/2 phosphorylation.

Role of MMP-1 (-519A/G, -1607 1G/2G), MMP-3 (Lys45Glu), MMP-7 (-181A/G), and MMP-12 (-82A/G) Variants and Plasma MMP Levels on Obesity-Related Phenotypes and Microvascular Reactivity in a Tunisian Population

“…According to the literature, MMP-3 could also be related to low-grade chronic inflammation in obesity. In line with this, Nakai et al [ 32 ] found that CRP, which is a low-grade systemic inflammation marker, induced MMP-1, MMP-3, and MMP-9 expression in adipocyte-differentiated 3T3-L1 cells. Our study provides, however, no significant association between the investigated polymorphisms and hs-CRP levels.…”

Association between Obesity and Periodontitis in US Adults: NHANES 2011–2014

“…Another mechanism involved oral bacteria. Nakai et al [31] suggested that obese individuals might have different oral bacteria than normal-weight individuals, which could contribute to the development of periodontitis. In vitro studies have shown that stimulation of adipocytes with C-reactive protein and inflammatory cytokines promotes adipocyte differentiation and increases the production of mature proteases such as matrix metalloproteinases.…”

Effect of Periodontitis and Toothbrushing Frequency on Obesity Onset: A Cohort Study

“…Additionally, periodontal disease is considered a chronic disease that spreads mildly, but systemically [32,33]. In an in vitro study, stimulation of adipocytes with CRP and inflammatory cytokines led to enhanced differentiation of adipocytes and elevated production of maturation-promoting proteinases such as matrix metalloproteinases [34]. Furthermore, induced experimental periodontitis in rats resulted in elevated levels of the monocyte chemotactic factor (monocyte chemoattractant protein-1) in serum and lipids in the liver [35].…”