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* The Department of Microbiology and Immunology,
Oral Health and Systemic Disease Research Group, University of Louisville, Louisville, KY 40202
IL-1 receptor antagonist (IL-1Ra), a natural inhibitor of IL-1β, has been shown to regulate the progression of a variety of inflammatory diseases. Although experimental studies and clinical trials have demonstrated the importance of IL-1Ra in chronic inflammatory diseases, the cellular mechanisms responsible for regulating the endogenous production of IL-1Ra by innate immune cells are currently unresolved. In the present study, we identify that glycogen-synthase kinase 3 (GSK3) regulates the production of the anti-inflammatory cytokine IL-1Ra via its ability to regulate the MAPK ERK1/2 in TLR-stimulated cells. Elucidation of the cell-signaling pathway by which GSK3 controlled ERK activity demonstrated that GSK3 inhibition resulted in an abrogation in the levels of the inhibitory residue serine 71 on Rac1 and increased the ability of Rac1 to interact with and activate p21-activated protein kinase. siRNA-mediated knockdown of Rac1 attenuated the ability of GSK3 inhibition to augment phopsho-ERK1/2 levels in LPS-stimulated immune cells. Moreover, inhibiting the ability of GSK3 to augment ERK1/2 activity abrogated enhanced IL-1Ra production by GSK3-inhibited cells. Our findings identify that GSK3 negatively regulates the levels of IL-1Ra produced by LPS-stimulated innate immune 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.
K.R., H.W., and M.M. designed and performed research, analyzed and interpreted, data and wrote the manuscript. C.A.G. and D.F.K. performed research and interpreted data.
1 The work was supported by a grant from the National Institute for Dental and Craniofacial Research (1R01DE017680–01A1) to MM.
2 K.R. and H.W. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Michael Martin, Oral Health and Disease Research Group, University of Louisville, Louisville, KY 40202. E-mail address: m0mart08{at}louisville.edu
4 Abbreviations used in this paper: IL-1Ra, IL-1 receptor antagonist; GSK3, glycogen-synthase kinase 3; PAK, phospho-p21-activated protein kinase.
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