Differential regulation of bradykinin receptor density, intracellular Ca2+, and prostanoid release in skin and foreskin fibroblasts. Effects of cell density and interleukin-1 alpha

1 Bradykinin (BK) receptors, cytosolic Ca2+, and prostanoids were studied i n human skin and foreskin fibroblasts. 2 B-max values of BK receptors were higher in foreskin than in skin fibrobl asts, increasing with cell densities in both cell types. IL-la-dependent re ceptor induction was blocked by cycloheximide. 3 BK-stimulated cytosolic Ca2+ elevation was higher in confluent than in no n-confluent cultures and larger in foreskin than in skin fibroblasts. Respo nses were not enhanced after IL-1-alpha-induced up-regulation of BK recepto rs. 4 Intrinsic prostanoid production was higher in foreskin than in skin fibro blasts at comparable cell densities. In foreskin, but not in skin fibroblas ts, BK stimulation increased the release of PGE(2) 10 fold and that of 6-ox o-PGF(1 alpha) 6-7 fold. 5 Preincubation with IL-lcr had a marked effect on prostanoid release in fo reskin fibroblasts only. Subsequent BK stimulation increased the release of PGE(2) and 6-oxo-PGF(1 alpha) 7-10 fold in skin fibroblasts while this inc rease was only 30% in foreskin fibroblasts. Release of TXA, reached values up to one third of the other prostanoids. The IL-1 alpha induced rise in BK -stimulated PGE(2) synthesis was fully abolished by specific inhibition of cyclo-oxygenase 2. 6 IL-1 alpha sensitized BK-stimulated prostanoid synthesis and modulated pr ostanoid patterns differently in fibroblasts from skin and foreskin. The IL -1 alpha effects on prostanoid release were not related to BK receptor numb ers nor to the BK-stimulated Ca2+ signal but appear to be due to induction of prostanoid synthesizing enzymes. Foreskin fibroblasts seem to be unique and significantly different from fibroblasts of other skin locations in res pect to their response to inflammation-associated kinins and cytokines.