The suppression of collagen production by increasing the cyclic (c) AMP content of cultured cells was examined vis-à-vis the β-adrenergic system. Cultured human fetal lung fibroblasts incubated for 6 h with the β-agonists isoproterenol or epinephrine produced ∼30% less collagen per cell than in the absence of the hormones. To demonstrate that the β-agonists were operating by their interaction with the β-receptor to stimulate adenylate cyclase to increase the intracellular content of cAMP, d- and l-isoproterenol were incubated separately with the cultured cells. Only l-isoproterenol increased intracellular cAMP and decreased collagen production. While 20 nM l-isoproterenol was effective, the d-isomer was ineffective even at 2μM. An increase in cAMP from 40 to 73 pmol/mg protein was effective in suppressing collagen production; increasing the cAMP content to much higher levels had little additional effect on collagen production. 3-Isobutyl-1-methylxanthine, an analog of theophylline that inhibits phosphodiesterase, potentiated the effect of isoproterenol in suppressing collagen production. Further support for the concept that isoproterenol suppressed collagen production by acting through the β-receptor was provided by the finding that only the l-isomer of propranolol, a β-blocker, was effective in blocking both the increase in intracellular cAMP and the suppression of collagen production caused by isoproterenol. These results demonstrate that collagen production in human fibroblasts can be regulated by the β-adrenergic system and indicate that when the cAMP content is increased beyond a threshold value, collagen production is suppressed. Since collagen production is sensitive to the small changes of cAMP content of cells brought about by β-stimulation in cultured cells, the results point to a possibly important mechanism for the regulation of collagen production in the body.
Richard A. Berg, Joel Moss, Bruce J. Baum, Ronald G. Crystal
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