Effect of 1, 25 dihydroxyvitamin D(3) on matrix metalloproteinases MMP-7, MMP-9 and the inhibitor TIMP-1 in pulmonary tuberculosis

Abstract

Matrix metalloproteinases (MMPs) play a vital role in the pathogenesis of several inflammatory diseases including tuberculosis through tissue remodeling. 1, 25(OH)(2)D(3) has several well recognized biological functions including suppression of MMP production. The influence of 1, 25(OH)(2)D(3) on MMP-7, MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1), production was studied in 43 pulmonary tuberculosis (PTB) patients and 44 healthy controls (HC). Peripheral blood mononuclear cells (PBMCs) were cultured with culture filtrate antigen (CFA) of Mycobacterium tuberculosis (MTB) and live MTB with or without 1, 25(OH)(2)D(3) (10(-7) M) for 48 h and the culture supernatants were assayed for MMP-7, MMP-9, TIMP-1 and cytokines IFN-gamma and TNF-alpha using ELISA. In HC and PTB, the levels of MMP-7, MMP-9 and TIMP-1 were not altered by CFA and live MTB stimulation in both groups. However, a significant decrease in the spontaneous production of MMP-7 (p=0.007), and an increase in MMP-9 (p=0.07) and TIMP-1 (p=0.0001) were observed in PTB patients as compared to HC. Vitamin D(3) significantly reduced the MMP-7 (p=0.0001) and MMP-9 (p=0.0001) and increased the TIMP-1 (p=0.005) level in antigen stimulated and unstimulated cultures of PTB as compared to HC. A significant positive correlation between MMP-9 and IFN-gamma was observed in unstimulated cultures of both HC (p=0.05) and PTB patients (p=0.0007). The present study suggests that 1, 25(OH)(2)D(3) suppresses the production of MMPs and enhances the level of TIMP-1 in tuberculosis. The present study suggests that 1, 25(OH)(2)D(3) may probably play an important role in the pathological process in tuberculosis by downregulating the levels of MMPs and upregulating the levels of TIMPs.