Figure 8

Signaling cascade activated by macrophage migration inhibitory factor (MIF). Rheumatoid arthritis (RA) synovial fibroblasts were pretreated 1 hour before stimulating with MIF (25 nM) for 25 minutes with different signaling inhibitors: the PKCδ inhibitor rottlerin, the pan-PKC inhibitor Ro-31-8425, the MEK (mitogen-activated protein kinase extracellular-signal-regulated kinase) inhibitor PD98059, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the Src inhibitor PP2, and the JNK inhibitor JNK II. (a) Upregulation of *p-JNK by MIF was inhibited by a Src inhibitor PP2. (b) The activation of the nuclear factor c-jun required the phosphorylation of JNK and Src. (c) Similarly, *p-PKCδ expression was Src and JNK pathway-dependent. Results are representative of four experiments using cells from four donors. JNK, c-jun N-terminal kinase; NS, nonstimulated; p-c-jun, phospho-c-jun; PKC, protein kinase C; rhMIF, recombinant human macrophage migration inhibitory factor.