As part of systemic inflammatory reactions, interleukin 6 (IL-6) induces acute phase protein (APP) genes through the Janus kinase (JAK)/signal transducer 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 expression of several APP genes in primary mouse hepatocytes. The APP-modifying action of EGF receptor (EGFR) was characterized in HepG2 cells.
Although EGF less effectively engages STAT proteins in these cells, it reduces expression of fibrinogen and haptoglobin, but stimulates production of
โฃ 1 -antichymotrypsin and induces transcription through the โฃ 1 -antichymotrypsin and C-reactive protein promoter. The stimulatory EGFR signal is insensitive to inhibition of JAKs and appears to involve Src kinases and STAT proteins as shown by inhibition through overexpression of C-terminal Src kinase (Csk) and transdominant negative STAT3, respectively. A mediator role of Src is supported by the ability of c-Src and v-Src to activate STATs and induce transcription through APP promoters. Src kinases have been observed in association with the IL-6 receptor; however, inhibition of Src kinases by Csk enhances IL-6-induced transcription. The Csk effect is attributed to prevention of Src kinases from phosphorylating gp130 at the docking site for the 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 ratio of receptor-activated STATs and Erks influence the level of stimulated or inhibited expression of individual APPs. (HEPATOLOGY 1999;30: 682-697.)
The increased production of acute phase plasma proteins (APP) by the liver in response to inflammation at extrahepatic sites is proposed to be mediated primarily by the concerted action of interleukin-1 (IL-1)-and IL-6-type cytokines and glucocorticoids. 1,2 However, the level of expression and cytokine regulation of individual APPs appears also to be additionally modulated by the action of endocrine hormones 3,4 and growth factors. [5][6][7] Few studies indicated a modest inhibitory effect of epidermal growth factor (EGF) on APPs in cultured hepatic cells. 8,9 However, EGF action on liver cells, in the context of inflammatory mediators as predicted to be present during acute phase response in vivo, during liver regeneration after partial hepatectomy, or during intrahepatic inflammation, [10][11][12] has not been determined. In particular, the suppressed execution of the hepatic acute phase response in regenerating liver 13 suggests an inhibitory effect of the proliferative signals delivered by growth factors, including EGF. Because under conditions of liver injury and regeneration, factors that promote hepatocyte growth and cytokines, which induce an acute phase response, temporally coexist in the liver, we hypothesize that growth factor receptor signals attenuate the action of IL-6 cytokines in a dominant fashion. The goal of this study was to charter the signaling pathways engaged by EGF that influence the liver cell response to IL-6 cytokines and affect expression of APPs.
Transcriptional induction of many APP genes depends on IL-6. The related cytokines, IL-11, leukemia inhibitory factor, and oncostatin M, can in part reproduce the effects of IL-6. 1 The functional redundancy of these cytokines is explained by the involvement of the common receptor subunit, gp130, in the signal transduction process by the respective cytokine receptor complex. 14 The activation of the DNA binding activity of signal transducer and activator of transcription (STAT)3 is the hallmark of gp130-dependent signaling 14,15 and is mediated by the receptor-associated Janus kinases, JAK1, JAK2, and TYK2. 16 The binding of activated STAT3 to STAT recognition sites within promoter regions of APP genes is suggested to be instrumental in controlling transcriptional induction.