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 mediator, interleukin-1 alpha (IL-1 alpha), stimulates protein kinase A (PKA) activity and adrenocorticotropic hormone (ACTH) secretion from AtT-20 cells without any detectable increase in intracellular cAMP accumulation. The present studies were conducted to determine if cAMP is involved 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 consistent 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 secretion were inhibited by 2'5'-DDA. Additional evidence was obtained using 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 PKA with the PKA inhibitor, H-8, blocked activation of PKA and ACTH secretion 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 alpha to induce ACTH secretion from AtT-20 cells.
Gwosdow
A R
AR
Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
O'Connell
N A
NA
Abou-Samra
A B
AB
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016048:Dideoxyadenosine / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000201:enzymology*; D011863:Radioimmunoassay
D007375:Interleukin-1; D016048:Dideoxyadenosine; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine