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Volume 271, Number 51, Issue of December 20, 1996 pp. 32586-32592
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Synergy between Tumor Necrosis Factor  and Interleukin 1 in Inducing Transcriptional Down-regulation of Muscarinic M₂ Receptor Gene Expression
INVOLVEMENT OF PROTEIN KINASE A AND CERAMIDE PATHWAYS

(Received for publication, May 9, 1996, and in revised form, July 11, 1996)

Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, Dovehouse Street, London SW3 6LY, United Kingdom

Stimulation of HEL 299 cells with tumor necrosis factor  (TNF-) or interleukin 1 (IL-1) had no effect on M₂ muscarinic receptor expression. However, the combination of these two cytokines markedly down-regulated muscarinic M₂ receptor protein and mRNA expression and uncoupled M₂ receptors from adenylyl cyclase. There was no effect of TNF- and IL-1 on the m2 muscarinic receptor mRNA stability, and nuclear run-on assays showed reduced m2 receptor gene transcription. Sequential cytokine addition suggests that the synergy involves postreceptor events. Although the cAMP-dependent protein kinase inhibitor H8 provided a significant protection against receptor down-regulation, the protein kinase C inhibitor GF109203X had no effect. The ceramide analog C₂-ceramide (N-acetylsphingosine) was without effect on m2 receptor expression. However, a strong synergistic effect was demonstrated when cells were treated with the combination of C₂-ceramide and TNF- or IL-1. TNF- and/or IL-1 combination also activated the 46- and 55-kDa c-Jun NH₂-terminal protein kinases and to a lesser extent p42 and p44 mitogen-activated protein kinase isoforms. Cycloheximide abolished the TNF- and IL-1 effect, suggesting that de novo protein synthesis is required for receptor down-regulation. These results suggest that the TNF- and IL-1 synergize to induce transcriptional down-regulation of the M₂ muscarinic receptor, which seems to be mediated through activation of both ceramide and cAMP-dependent protein kinase pathways. Furthermore, these results suggest that M₂ receptor expression is under the control of a cytokine network.

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