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c-Jun Controls the Ability of IL-12 to Induce IL-10 Production from Human Memory CD4⁺ T Cells¹

Carlos A. Garcia^*, Huizhi Wang^*, Manjunatha R. Benakanakere, Elyse Barrett^*, Denis F. Kinane and Michael Martin^2,*,

^* Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292; and Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, KY 40292

IL-12p70 is an immunoregulatory cytokine that has been shown to induce IL-10 production from CD4⁺ T cells, yet the underlying cellular mechanisms controlling this process are poorly understood. In the present study, we demonstrate that IL-12p70 induces IL-10 production from human memory CD4⁺ T cells via a PI3K-dependent signaling mechanism. Specifically, stimulation of human memory CD4⁺ T cells in the presence of IL-12p70 lead to increased PI3K activity and the subsequent phosphorylation and inactivation of the downstream constitutively active serine/threonine kinase, glycogen synthase kinase-3β (GSK3β). Inhibition of PI3K prevented the inactivation of GSK3β by IL-12p70, as well as the subsequent ability of IL-12p70 to augment IL-10 levels by memory CD4⁺ T cells. Moreover, ectopic expression of a constitutively active form of GSK3β abrogated the ability of IL-12p70 to increase IL-10 production by TCR-stimulated CD4⁺ T cells. In contrast, direct inhibition of GSK3 mimicked the effect of IL-12p70 on IL-10 production by memory CD4⁺ T cells. Analysis of downstream transcription factors identified that the ability of IL-12p70 to inactivate GSK3β lead to increased levels of c-Jun. The ability of IL-12p70 to inactivate GSK3β and induce c-Jun levels was required for IL-12 to augment IL-10 production by human memory CD4⁺ T cells, since small interfering RNA-mediated gene silencing of c-Jun abrogated this process. These studies identify the cellular mechanism by which IL-12 induces IL-10 production from human memory CD4⁺ T cells.

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 research was supported by Grant R01DE017680 from the National Institute of Dental Research.

² Address correspondence and reprint requests to Dr. Michael Martin, University of Louisville School of Dentistry, 501 South Preston Street, Room 211A, Louisville, KY 40202. E-mail address: m0mart08{at}louisville.edu

³ Abbreviations used in this paper: GSK3β, glycogen synthase kinase-3β; siRNA, small interfering RNA.