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Morphine Withdrawal Inhibits IL-12 Induction in a Macrophage Cell Line through a Mechanism That Involves cAMP¹

Jennifer Kelschenbach, Jana Ninkovic, Jinghua Wang^*, Anitha Krishnan^*, Richard Charboneau, Roderick A. Barke^*, and Sabita Roy^2,*,,

^* Department of Surgery and Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455; and Veterans Affairs Medical Center, Minneapolis, MN 55417

There are very few studies that examine the effects that morphine withdrawal has on immune functioning, and of these even fewer describe the mechanisms by which withdrawal brings about these changes. Our previous work demonstrated that morphine withdrawal contributed to Th cell differentiation by biasing cells toward the Th2 lineage. A major finding from these studies was that IL-12 was decreased following withdrawal, and it was concluded that this decrease may be a mechanism by which morphine withdrawal is mediating Th2 polarization. Therefore, it was the aim of the current studies to develop an in vitro model to examine the process of morphine withdrawal and to understand the signaling mechanisms that withdrawal may use to effect IL-12 production through the use of this model. It was demonstrated and concluded that morphine withdrawal may be effecting IL-12 production by increasing cAMP levels, which activates protein kinase A. Protein kinase A activation then prevents the phosphorylation and subsequent degradation of IB, which in turn prevents translocation of the NF-B p65 subunit to the nucleus to transactivate the IL-12 p40 gene, ultimately resulting in decreased IL-12 production following LPS stimulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01DA12104, R01 DA022935, K02 DA015349, P50DA11806 (to S.R.), and T32 DA07097 (to J.K. and J.N.).

² Address correspondence and reprint requests to Dr. Sabita Roy, Departments of Surgery and Pharmacology, University of Minnesota, MMC 195, 420 Delaware Street, Minneapolis, MN 55455. E-mail address: royxx002{at}umn.edu

³ Abbreviations used in this paper: MOR, µ opioid receptor; IKK, IB kinase; PKA, protein kinase A.