DIVERGENCE IN MACROPHAGE INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) SYNTHESIS INDUCED BY TNF-ALPHA AND PROSTAGLANDIN E(2)

Increased synthesis of insulin-like growth factor I (IGF-I), a fibrobl ast 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 E(2) (PGE(2)) is known to inhibit macrophage cytocidal activity, its possible reciproca l enhancement of IGF-I synthesis was examined. PGE(2) or dibutyryl cyc lic AMP (dbcAMP) stimulated the synthesis of IGF-I similarly to TNF-al pha in magnitude and time course. TNF-alpha did not increase IGF-I syn thesis by first inducing PGE(2) synthesis, because indomethacin was un able to block the effect of TNF-alpha. PGE(2) did not stimulate IGF-I synthesis by first inducing TNF-alpha production, because 1) anti-TNF- alpha Ab did not block PGE(2)-induced IGF-I synthesis, and 2) PGE(2) d own-regulated TNF-alpha mRNA levels and did not affect levels of the c ytokine in supernatants. Moreover, the difference in the induction of IGF-I was observed at the level of signal transduction, in that PGE(2) and dbcAMP increased cAMP-dependent protein kinase (PKA) activity, wh ereas TNF-alpha stimulated the mitogen-activated protein (MAP) kinase pathway. Divergence between the two pathways was also noted in the reg ulation of IGF-I at the mRNA level, and an additive effect on IGF-I sy nthesis was observed when cells were incubated with the combination of TNF-alpha plus PGE(2) or dbcAMP. Collectively, these data suggest tha t TNF-alpha and PGE(2) stimulate IGF-I synthesis in macrophages by two separate pathways, and that PGE(2) acts as a positive stimulus for IG F-I synthesis through a cyclic AMP/PKA pathway.