Interleukin-6-induced STAT3 transactivation and Ser727 phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4 as signal transduction components

Abstract

In the present study, signal transducer and activator of transcription 3 (STAT3) Ser(#( phosphorylation and transactivation was investigated in relation to activation of mitogen-activated protein (MAP) kinase family members including extracellularsignal-regulated protein kinase (ERK)-1, c-Jun N-terminal kinase (JNK)-1 and p38 (' reactivating kinase ') in response to interleukin (IL)-6 stimulation. Although IL-6 can activate ERK-1 in HepG2 cells, STAT3 transactivation and Ser(#( phosphorylation were not reduced by using the MAP kinase\ERK kinase (MEK) inhibitor PD98059 or by overexpression of dominant-negative Raf. IL-6 did not activate JNK-1 in HepG2 cells and STAT3 was a poor substrate for JNK-1 activated by anisomycin, excluding a role for JNK1 in IL-6-induced STAT3 activation. However, SEK-1\MKK-4 [where SEK-1 stands for stress-activated protein kinase (SAPK)\ERK kinase 1, and MKK-4 stands for MAP kinase kinase 4] was activated in response to IL-6 and overexpression of dominant-negative SEK-1\MKK-4(A-L) reduced

Regulation of rat heme oxygenase-1 expression by interleukin-6 via the Jak/STAT pathway in hepatocytes

“…7). This is in agreement with a study performed in HepG2 cells where IL-6 activated ERK1 and slightly p38 but not Jun N-teminal kinase-1 (JNK1) [34]. The residue within gp130 necessary for ERK activation was identified to be Tyr 759 [24].…”

“…[3][4][5] indicating that in addition to the Jak/STAT pathway, MAPK and PI3K/PKB cascades may also be involved in IL-6 signaling [15]. Moreover, several MAP kinases as well as PI3K were shown to contribute to STAT3 phosphorylation at Ser 727 [34,35]. In our study, IL-6 treatment led to phosphorylation of ERK1/2 and did not induce c-Jun or p38 MAPK phosphorylation in PHC (Fig.…”

Stat3 confers resistance against hypoxia/reoxygenation-induced oxidative injury in hepatocytes through upregulation of Mn-SOD

“…Signal transducer and activator of transcription-3 (Stat3) is a latent cytoplasmic transcription factor that functions as an intracellular effector activated by various ligands including members of the interleukin-6 (IL-6) family, EGF and PDGF, and by a number of receptor-and nonreceptor-tyrosine kinases [12][13][14][15][16]. Stat3 was originally investigated as a molecule that was capable of selectively interacting with an enhancer element in the promoter of acute-phase response genes following stimulation by inteleukin-6 (IL-6) [17,18].…”

New anti-inflammatory agents to reduce atherosclerosis

“…In the first case, the tyrosine phosphorylation is mediated by the tyrosine kinase activity of the stimulated IL-6 receptor complex (IL-6Ra/gp130/ JAK) (Schindler et al, 1995). In the other case, recent reports indicate that the serine phosphorylation is mediated by protein kinase C-delta, which in turn is activated by a signal transduction pathway consisting of Vav, Rac-1, MEKK and SEK-1 (Schuringa et al, 2000). In this study, we have shown that statins reduce IL-6-induced CRP expression via the inhibition of protein geranylgeranylation.…”