Transforming growth factor-beta suppresses macrophage-induced mesangial cell fibronectin expression

Background. We have previously shown that macrophages are able to promote p rosclerotic responses in rat mesangial cells. Th2-type cytokines, including interleukin-10(IL-10), IL-13, and IL-4 as well as transforming growth fact or-beta (TGF-P), are known to have suppressive effects on various aspects o f macrophage function. In the current study, we investigated the effect of TGF-beta pretreatment on the ability of macrophages to induce fibronectin e xpression. Results. Conditioned medium from TGF-beta pretreated macrophages (MPCMTGF) induced lower fibronectin levels in mesangial cells in both the secreted an d cell-associated forms, compared with conditioned medium from standard mac rophages (MPCM) (5.5 +/- 0.2 vs. 3.4 +/- 0.3 and 4.05 +/- 0.45 vs. 2.3 +/- 0.2 fold increase over medium alone for MPCM versus MPCMTGF in supernatants and cell lysates, respectively), Northern blot analysis demonstrated that fibronectin message was marginally reduced to 0.88 +/- 0.04 (P < 0.03 vs. M PCM, N = 3) of MPCM induced levels. However, mesangial cell transin mRNA le vels induced in response to MPCMTGF were 2.29 +/- 0.47-fold greater than th ose induced by standard MPCM (P = 0.03 vs. MPCM, N = 4), TIMP-1 mRNA levels were also increased in response to MPCMTGF, but only by 1.43 +/- 0.1-fold (P = 0.02 vs. MPCM, N = 5). Casein-FITC digestion studies confirmed that MP CM,GF stimulated more mesangial cell caseinolytic activity than did MPCM. I n addition, MPCM-mediated up-regulation of mesangial cell TGF-beta mRNA and protein expression was significantly reduced in response to conditioned me dium from macrophages pretreated with TGF-beta. Conclusion. This study suggests that TGF-beta is able to regulate negativel y the profibrotic effects of macrophages on mesangial cells by both enhanci ng matrix degradation and reducing synthesis.