CARDIAC FIBROBLASTS ARREST AT THE G1 S RESTRICTION POINT IN RESPONSE TO INTERLEUKIN (IL)-1-BETA - EVIDENCE FOR IL-1-BETA-INDUCED HYPOPHOSPHORYLATION OF THE RETINOBLASTOMA PROTEIN/

Although responsible for only approximately one-third of the overall m yocardial mass, the interstitial fibroblasts of the heart serve a fund amental role in establishing the functional integrity of myocardium an d are the major source of myocardial extracellular matrix production. Their importance in clinical medicine is underscored by the observatio n that fibroblast numbers increase in response to several pathologic c ircumstances that are associated with an increase in extracellular mat rix production such as long standing hypertension and myocardial injur y/infarction. Up to the present time, however, there has been little i nformation available on either the kinetics of the cardiac fibroblast cell cycle, or the fundamental mechanisms that regulate its entry into and exit from the cell cycle. Previous work from our laboratory exami ning the effects of interleukin (IL)-1 beta on myocardial growth and g ene expression in culture indicated that cardiac fibroblasts have a di minished capacity to synthesize DNA in response to mitogen in the pres ence of this cytokine. The mechanism of IL-1 beta action was not clear , however, and could have resulted from action at several different po ints in the cell cycle, The investigations described in this report in dicate that IL-1 beta exerts its effect on the fibroblast cell cycle a t multiple levels through altering the expression of cardiac fibroblas t cyclins, cyclin-dependent kinases, and their inhibitors, which ultim ately affect the phosphorylation of the retinoblastoma gene product.