Pro-inflammatory cytokines stimulate mitogen-activated protein kinase subfamilies, increase phosphorylation of c-Jun and ATF2 and upregulate c-Jun protein in neonatal rat ventricular myocytes
A. Clerk et al., Pro-inflammatory cytokines stimulate mitogen-activated protein kinase subfamilies, increase phosphorylation of c-Jun and ATF2 and upregulate c-Jun protein in neonatal rat ventricular myocytes, J MOL CEL C, 31(12), 1999, pp. 2087-2099
Pro-inflammatory cytokines may be important in the pathophysiological respo
nses of the heart. We investigated the activation of the three mitogen-acti
vated protein kinase (MAPK) subfamilies [c-Jun N-terminal kinases (JNKs), p
38-MAPKs and extracellularly-responsive kinases (ERKs)] by interleukin-1 be
ta (IL-1 beta) or tumour necrosis factor alpha (TNF alpha) in primary cultu
res of myocytes isolated from neonatal rat ventricles. Both cytokines stimu
lated a rapid (maximal within 10 min) increase in JNK activity. Although ac
tivation of JNKs by IL-1 beta was transient returning to control values wit
hin 1 h, the response to TNF alpha was sustained. IL-1 beta and TNF alpha.
also stimulated p38-MAPK phosphorylation, but the response to IL-1 beta was
consistently greater than TNF alpha, Both cytokines activated ERKs, but to
a lesser degree than that induced by phorbol eaters. The transcription fac
tors, c-Jun and ATF2, are phosphorylated by the MAPKs and are implicated in
the upregulation of c-Jun. IL-1 beta and TNF alpha stimulated the phosphor
ylation of c-Tun and ATF2. However, IL-1 beta induced a greater increase in
c-Jun protein. Inhibitors of protein kinase C (PKC) (Ro318220, GF109203X)
and the ERK cascade (PD98059) attenuated the increase in c-Jun induced by I
L-1 beta, but LY294002 (an inhibitor of phosphatidylinositol 3' kinase) and
SB203580 (an inhibitor of p38-MAPK, which also inhibits certain JNK ( isof
orms) had no effect. These data illustrate that some of the pathological ef
fects of IL-1 beta and TNF alpha may be mediated through the MAPK cascades.
and that the ERK cascade, rather than JNKs or p38-MAPKs, are implicated in
the upregulation of c-Tun by IL-1 beta. (C) 1999 Academic Press.