DIFFERENTIAL SIGNALING PATHWAYS IN PLATELET-ACTIVATING FACTOR-INDUCEDPROLIFERATION AND INTERLEUKIN-6 PRODUCTION BY RAT VASCULAR SMOOTH-MUSCLE CELLS

Vascular smooth muscle cells (SMCs) can be induced to proliferate in r esponse to several cytokines and growth factors, including interleukin (IL)-6. Platelet-activating factor (PAF) also has been shown to induc e SMC proliferation. Because PAF can stimulate IL-6 production in mono cytes, macrophages, and endothelial cells, our study was undertaken to determine whether PAF could induce IL-6 production by SMCs and to def ine the underlying signaling pathways. Exposure of rat aortic SMCs to picomolar concentrations of PAF resulted in enhanced production of IL- 6. The effect was concentration dependent, selective for the active fo rm of PAF, and mediated by specific PAF receptors. Pretreatment of the cells with Bordatella pertussis toxin (PTX) prevented the effect of P AF, suggesting the involvement of alpha(i)-type subunits of G proteins in the signal-transduction path way. PAF-dependent IL-6 production wa s also prevented by inhibition of tyrosine kinases with genistein or e rbstatin. Inhibition of eicosanoid production by blocking either phosp holipase A(2) or cyclooxygenase also abrogated the effect of PAF on IL -6 production. Moreover, inhibition of Ca2+-calmodulin activity with W 7 or blocking of calcium channels with verapamil or nifedipine prevent ed PAF-mediated enhancement of IL-6 production. Whereas PAF-induced si gnal-transduction pathways leading to IL-6 production and SMC prolifer ation were partially common, they appeared to diverge downstream of PL A(2) activation: inhibition of cyclooxygenase had no effect on prolife ration, whereas augmentation of cyclic adenosine monophosphate (cAMP) levels or activation of protein kinase A inhibited proliferation, in c ontrast to IL-6 production. Our findings suggest a role for PAF in mod ulating vascular function by stimulating local production of IL-6 by S MCs and promoting their proliferation. The two effects are, however, a ssociated with partially divergent signaling pathways and may not be c ausally related.