INTERLEUKIN-1 INCREASES PROTEIN-KINASE-A ACTIVITY BY A CAMP-INDEPENDENT MECHANISM IN ATT-20 CELLS

A recent study from this laboratory has shown that the inflammatory me diator, interleukin-1 alpha (IL-1 alpha), stimulates protein kinase A (PKA) activity and adrenocorticotropic hormone (ACTH) secretion from A tT-20 cells without any detectable increase in intracellular cAMP accu mulation. The present studies were conducted to determine if cAMP is i nvolved in IL-1 alpha activation of PKA and if PKA is responsible for IL-1 alpha-induced ACTH release from AtT-20 cells. The data are consis tent with a novel, mechanism of PKA. activation that does not involve cAMP. Inhibition of adenylate cyclase with 2'5'-dideoxyadenosine (2'5' -DDA) did not affect IL-1 alpha-induced increases in PKA activity and ACTH secretion. In contrast, CRF-stimulated PKA activity and ACTH secr etion were inhibited by 2'5'-DDA. Additional evidence was obtained usi ng the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) . IBMX did not alter IL-1 alpha-induced PKA activity or ACTH secretion , yet IBMX potentiated CRF-induced cAMP accumulation. Inhibition of PK A with the PKA. inhibitor, H-8, blocked activation of PKA and ACTH sec retion by both IL-1 alpha and CRF in AtT-20 cells. These observations demonstrate that 1) the mechanism of IL-1 alpha activation of PKA. is independent of adenylate cyclase or cAMP and 2) PKA is used by IL-1 al pha to induce ACTH secretion from AtT-20 cells.