WISP1 induces the expression of macrophage migration inhibitory factor (MIF) in human lung fibroblasts through Src kinases and EGFR-activated signaling pathways.

Wnt1-inducible signaling protein 1 (WISP1/CCN4) is a secreted matricellular protein that is implicated in lung and airway remodeling. The macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been associated with chronic lung diseases. In this study, we aimed to investigate the WISP1 signalling pathway and its ability to induce the expression of MIF in primary cultures of fibroblasts from normal human lung (HLFs). Our results showed that WISP1 significantly stimulated the expression of MIF in a concentration- and time-dependent fashion. In WISP1-induced expression of MIF, αvβ5 integrin and chondroitin sulphate proteoglycans as well as Src tyrosine kinases, MAP kinases, PI3K/Akt, PKC and NF-κB were involved. WISP1-induced expression of MIF was attenuated in the presence of Src kinases inhibitor PP2 or the MIF tautomerase activity inhibitor, ISO-1. Moreover, WISP1 significantly increased the phosphorylation and activation of EGFR through transactivation by Src kinases. WISP1 also induced the expression of MIF receptor CD74 and co-receptor CD44, through which MIF exerts its effects on HLFs. In addition, it was found that MIF induced its own expression, as well as its receptors CD74/CD44, acting in an autocrine manner. Finally, WISP1-induced MIF promoted the expression of COX-2, PGE2, IL-6 and MMP-2 demonstrating the regulatory role of WISP1-MIF axis in lung inflammation and remodeling involving mainly integrin αvβ5, Src kinases, PKC, NF-κB and EGFR. The specific signalling pathways involved in WISP1-induced expression of MIF may be proven excellent candidates as novel targets to control inflammation in chronic lung diseases.