Modulation of hepatic acute phase gene expression by epidermal growth factor and Src protein tyrosine kinases in murine and human hepatic cells

As part of systemic inflammatory reactions, interleukin 6 (IL-6) induces ac ute phase protein (APP) genes through the Janus kinase (JAK)/signal transdu cer and activator of transcription (STAT) pathway Epidermal growth factor ( EGF), which contributes to the regenerative process after liver injury and also activates STATs, does not induce but attenuates IL-6-stimulated expres sion of several APP genes in primary mouse hepatocytes. The APP-modifying a ction of EGF receptor (EGFR) was characterized in HepG2 cells, Although EGF less effectively engages STAT proteins in these cells, it reduces expressi on of fibrinogen and haptoglobin, but stimulates production of alpha(1)-ant ichymotrypsin and induces transcription through the alpha(1)-antichymotryps in and C-reactive protein promoter. The stimulatory EGFR signal is insensit ive to inhibition of JAKs and appears to involve Src kinases and STAT prote ins as shown by inhibition through overexpression of C-terminal Src kinase (Csk) and transdominant negative STAT3, respectively. A mediator role of Sr c is supported by the ability of c-Src and v-Src to activate STATs and indu ce transcription through APP promoters. Src kinases have been observed in a ssociation with the IL-6 receptor; however, inhibition of Src kinases by Cs k enhances IL-6-induced transcription. The Csk effect is attributed to prev ention of Src kinases from phosphorylating gp130 at the docking site for th e signal-moderating protein tyrosine phosphatase SHP-2. The inhibitory EGFR signal on APP expression correlates with the activation of Erk1 and Erk2. The study shows a dual signaling function for EGFR and suggests that the ra tio of receptor-activated STATs and Erks influence the level of stimulated or inhibited expression of individual APPs.