p38 MAPK and NF-κB Collaborate to Induce Interleukin-6 Gene Expression and Release

Abstract

In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-B, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IB kinase (IKK)-␤ and stimulated its abilities to phosphorylate IB and to activate NF-B. MKK6(Glu) induced NF-B-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-␣, which activates both NF-B and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-␣ was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis. TNF-␣-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-␤ activated protein kinase (Tak1), which is known to activate p38 and NF-B in other cell types. Thus, by stimulating both p38 and NF-B, Tak1-activating cytokines, like TNF-␣, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38.

Transforming growth factor-β1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-κB, JNK, and Ras signaling pathways

“…TNF-a-mediated IL-6 induction occurs through TGF-b activating kinase 1 (TAK1) stimulation of NF-kB in which p38 MAPK acts as an activator of IkB kinases (Craig et al, 2000). TAK1 is a MAPK kinase kinase that can be activated by TGF-b and bone morphogenic protein.…”

“…It has been documented that IL-6 activation by IL-1b or TNF-a is mediated through the p38 MAPK pathway, and p38 MAPK participates in TGF-b1-induced gene expression (Hanafusa et al, 1999;Craig et al, 2000;Wery-Zennaro et al, 2000). Based on these reports, we explored whether the p38 MAPK signaling is involved in the TGF-b1-induced IL-6 expression in prostate cancer cells.…”

“…NF-kB is activated by p38 MAPK and required for TGF-b1-mediated IL-6 induction NF-kB is a key regulatory factor for IL-6 gene transcription and its activation by various cytokines occurs through p38 MAPK in many types of human cells (Asschert et al, 1999;Craig et al, 2000). To evaluate the involvement of NF-kB activation in TGFb1-mediated IL-6 induction, we examined whether TGF-b1 stimulates nuclear translocation of NF-kB.…”

Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo

“…5), fosters cardioprotection from I/R injury in TG mice (36). Also, NF B, which is known to induce expression of several cardioprotective genes, such as inducible nitric-oxide synthase, cyclooxygenase-2, superoxide dismutase, and interleukin-6 (13,(42)(43)(44), might confer cardioprotection in MKK6 mice. It is interesting to note that Bcl-2 fosters NF B activation in cardiac myocytes (45), providing a potential linkage in the mechanisms by which these two signaling proteins mediate protection.…”

Activation of NF-κB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes

“…Given the fact that the transmission of extracellular signals are mediated by a signaling network, rather than a single signaling pathway, and that many factors are involved in hypertrophic growth of cardiomyocytes, the growth of cardiomyocytes is likely the result of cooperation among many signaling pathways (54,55). For instance, recent studies showed that activation of the p38 pathway may contribute to NF-B transcriptional activity (55)(56)(57)(58), most likely through enhancing expression of NF-B target genes (56,58). Future studies are needed to explore the interplay between the NF-B and other signaling pathways and to elucidate the in vivo role of NF-B activation in cardiomyocyte hypertrophy.…”