Divergence in macrophage insulin-like growth factor-I (IGF-I) synthesis induced by TNF-alpha and prostaglandin E2.
Increased synthesis of insulin-like growth factor I (IGF-I), a fibroblast growth factor, is induced in murine macrophages by TNF-alpha. TNF-alpha also induces macrophages to express cytocidal activity, but only during costimulation with IFNs. Since prostaglandin E2 (PGE2) is known to inhibit macrophage cytocidal activity, its possible reciprocal enhancement of IGF-I synthesis was examined. PGE2 or dibutyryl cyclic AMP (dbcAMP) stimulated the synthesis of IGF-I similarly to TNF-alpha in magnitude and time course. TNF-alpha did not increase IGF-I synthesis by first inducing PGE2 synthesis, because indomethacin was unable to block the effect of TNF-alpha. PGE2 did not stimulate IGF-I synthesis by first inducing TNF-alpha production, because 1) anti-TNF-alpha Ab did not block PGE2-induced IGF-I synthesis, and 2) PGE2 down-regulated TNF-alpha mRNA levels and did not affect levels of the cytokine in supernatants. Moreover, the difference in the induction of IGF-I was observed at the level of signal transduction, in that PGE2 and dbcAMP increased cAMP-dependent protein kinase (PKA) activity, whereas TNF-alpha stimulated the mitogen-activated protein (MAP) kinase pathway. Divergence between the two pathways was also noted in the regulation of IGF-I at the mRNA level, and an additive effect on IGF-I synthesis was observed when cells were incubated with the combination of TNF-alpha plus PGE2 or dbcAMP. Collectively, these data suggest that TNF-alpha and PGE2 stimulate IGF-I synthesis in macrophages by two separate pathways, and that PGE2 acts as a positive stimulus for IGF-I synthesis through a cyclic AMP/PKA pathway.
Fournier
T
T
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA.
Riches
D W
DW
Winston
B W
BW
Rose
D M
DM
Young
S K
SK
Noble
P W
PW
Lake
F R
FR
Henson
P M
PM
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D004357:Drug Synergism; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D003994:Bucladesine; D007334:Insulin-Like Growth Factor I; D003513:Cycloheximide; D015232:Dinoprostone