STIMULATION OF AGED HUMAN LUNG FIBROBLASTS BY EXTRACELLULAR ATP VIA SUPPRESSION OF ARACHIDONATE METABOLISM

The mitogenic effect of extracellular ATP on IMR-90 human fibroblasts subjected to in vitro aging was studied. ATP stimulated DNA synthesis and cell proliferation in young cells as much as epidermal growth fact or (EGF) or insulin, while it stimulated aged cells to a much greater extent than seen for any other growth factor tested. When combined wit h EGF or insulin, ATP restored the greatly reduced mitogenic responsiv eness of aged cells nearly to the level noted for young cells. Additio n of prostaglandin E2 or other agents that elevate cAMP levels resulte d in inhibition of DNA synthesis stimulated by EGF or insulin. Further more, the basal release of arachidonic acid and prostaglandin E2 and t he endogenous levels of cAMP rose during aging and became much greater than in young cells. All three of these changes were suppressed by ex tracellular ATP. ATP-dependent suppression of cAMP accumulation was pe rtussis toxin-sensitive. Protein kinase C down-regulation inhibited ar achidonate metabolism and enhanced DNA synthesis stimulated by ATP. Th ese studies suggest that ATP exerts its mitogenic effect, especially o n aged IMR-90 cells, at least partially by suppression of arachidonate metabolism.