Nakai Kumiko, Tanaka Hideki, Yamanaka Kazuhiro, Takahashi Yumi, Murakami Fumiko, Matsuike Rieko, Sekino Jumpei, Tanabe Natsuko, Morita Toyoko, Yamazaki Yoji, Kawato Takayuki, Maeno Masao
Department of Oral Health Sciences, Nihon University School of Dentistry, Tokyo, Japan.
Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
Int J Med Sci. 2017 Apr 9;14(5):484-493. doi: 10.7150/ijms.18059. eCollection 2017.
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.
肥胖与炎症之间的关联在流行病学研究中已有充分记载。细胞外基质（ECM）蛋白的蛋白水解参与脂肪组织的增大，而基质金属蛋白酶（MMPs）共同裂解所有ECM蛋白。在此，我们研究了炎症生物标志物C反应蛋白（CRP）对脂肪细胞分化的3T3-L1细胞中MMPs及其天然抑制剂金属蛋白酶组织抑制剂（TIMPs）表达的影响。我们分析了作为CRP受体候选者的Fcγ受体（FcγR）IIb和FcγRIII的表达，以及可作为FcγRII和FcγRIII阻滞剂的抗CD16/CD32抗体对CRP诱导的MMP和TIMP表达改变的影响。此外，我们在有或没有抗CD16/CD32抗体的情况下，研究了CRP对参与MMP和TIMP表达的丝裂原活化蛋白激酶（MAPK）信号激活的影响。用CRP刺激可增加MMP-1、MMP-3、MMP-9、MMP-11、MMP-14和TIMP-1的表达，但不影响MMP-2、TIMP-2和TIMP-4的表达；未检测到TIMP-3的表达。脂肪细胞分化的3T3-L1细胞表达FcγRIIb和FcγRIII；这种表达在CRP刺激下上调。抗CD16/CD32抗体抑制CRP诱导的MMPs（MMP-11除外）和TIMP-1的表达。CRP诱导细胞外信号调节激酶（ERK）1/2和p38 MAPK的磷酸化，但不影响SAPK/JNK的磷酸化，抗CD16/CD32减弱了CRP诱导的p38 MAPK的磷酸化，但不影响ERK1/2的磷酸化。这些结果表明，CRP通过增加脂肪细胞中多种MMPs和TIMP-1的产生促进脂肪组织中的ECM周转。此外，FcγRIIb和FcγRIII参与CRP诱导的MMPs和TIMP-1的表达以及CRP诱导的p38磷酸化，而不依赖FcγR的途径可能调节CRP诱导的MMP-11表达和CRP诱导的ERK1/2磷酸化。
