Interleukin-1beta-induced apoptosis through adenylyl cyclase and ERK1/2 inhibition in primary cultured thyroid cells.
The programmed cell death plays a crucial role in the regulation of numerous physiological and pathological phenomena. In this study, we show that interleukin-1 beta (IL-1beta) induces an early production of endogenous ceramides via N-sphingomyelinase (N-Smase) as well as an inhibition of adenylyl cyclase activity in pig thyroid cells. This effect is followed by a down-regulation of the extracellular signal-regulated protein kinase (ERK1/2) phosphorylation, an activation of caspase-3, and ends by setting up the programmed cell death. The permeable exogenous C(2)-ceramide reproduces IL-1beta effects on: (i) inhibition of adenylyl cyclase activity, (ii) down-regulation of ERK1/2 phosphorylation, (iii) activation of caspase-3, and (iv) apoptosis in pig thyroid cells. Cell treatment with a PKA inhibitor down-regulates ERK1/2 phosphorylation. Furthermore, inhibition of ERK1/2 signaling pathway by U-0126 enhances caspase-3 activity and sets up programmed cell death. Both IL-1beta and exogenous C(2)-ceramide effects are reproduced by U-0126 so illustrating the implication of ERK1/2 down-regulation in both caspase-3 activation and apoptosis induction. Our study shows for the first time that endogenous ceramides are important second messengers in IL-1beta-induced apoptosis in pig thyroid cells through inhibition of adenylyl cyclase and ERK1/2 activities.
El Btaouri
Hassan
H
Laboratoire de Biochimie, UMR-CNRS 6198, IFR 53, UFR Sciences Exactes et Naturelles, BP 1039, Université de Reims Champagne-Ardenne, 51687 Reims Cedex 2, France. hassan.elbtaouri@univ-reims.fr
Rath
Geraldine
G
Morjani
Hamid
H
Schneider
Christophe
C
Petitfrere
Emmanuelle
E
Antonicelli
Franck
F
Martiny
Laurent
L
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis; D000242:Cyclic AMP; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D013552:Swine; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*
D000067956:Adenylyl Cyclase Inhibitors; D002518:Ceramides; D007375:Interleukin-1; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000262:Adenylyl Cyclases