TNF‐α induces VCAM‐1 expression via PKCδ/Src/EGFR transactivation linking to AP‐1 and NF‐¿B in human renal mesangial cells

Abstract

In glomerular cells, TNF‐α can induce adhesion molecule expression and then attracts monocytes adhesion. However, the mechanisms underlying TNF‐α ‐induced VCAM‐1 expression in human renal mesangial cells (HRMCs) remain unclear. Western blot, RT‐PCR, and monocytes adhesion analyses showed that in HRMCs, TNF‐α induced VCAM‐1 mRNA and protein expression in a time‐dependent manner, which were attenuated by the inhibitors of PKC (GF109203X and rottlerin), c‐Src (PP1), EGF receptor (AG1478), PI3K (LY294002), p38 MAPK (SB202190) and JNK (SP600125), or transfection with siRNA of c‐Src, Akt, p38 MAPK, and JNK2. These results suggest that EGFR transactivation participates in VCAM‐1 expression induced by TNF‐α. Accordingly, TNF‐α ‐stimulated phosphorylation of p38 MAPK and JNK was inhibited by pretreatment with GF109203X, rottlerin, PP1, AG1478, LY294002, SB202190, or SP600125. TNF‐α induced VCAM‐1 expression was blocked by selective inhibitors of AP‐1 (tanshinone IIA) and NF‐¿B (Bay11‐7082). Moreover, TNF‐α ‐stimulated activation of VCAM‐1 promoter activity was blocked by these selective inhibitors. Taken together, these results suggest that in HRMCs, PKCδ/c‐Src‐dependent EGFR transactivation, PI3K/Akt, p38 MAPK, JNK activation linking to AP‐1 and NF‐¿B is involved in TNF‐α‐induced VCAM‐1 expression and monocytes adhesion.