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Endogenous IL-32 Controls Cytokine and HIV-1 Production¹

Marcel F. Nold^*,, Claudia A. Nold-Petry^*, Gregory B. Pott^*, Jarod A. Zepp^*, Milene T. Saavedra^*, Soo-Hyun Kim^*, and Charles A. Dinarello^2,*

^* Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; Department of Pediatrics, Hospital of the J.W. Goethe University, Frankfurt am Main, Germany; and Department of Biomedical Science and Technology, Konkuk University, Seoul, Republic of Korea

IL-32, a proinflammatory cytokine that activates the p38MAPK and NF-B pathways, induces other cytokines, for example, IL-1β, IL-6, and TNF-. This study investigated the role of endogenous IL-32 in HIV-1 infection by reducing IL-32 with small interfering (si)RNA in freshly infected PBMC and in the latently infected U1 macrophage cell line. When PBMC were pretreated with siRNA to IL-32 (siIL-32), IL-6, IFN-, and TNF- were reduced by 57, 51, and 36%, respectively, compared with scrambled siRNA. Cotransfection of NF-B and AP-1 reporter constructs with siIL-32 decreased DNA binding of these transcription factors by 42 and 46%, respectively. Cytokine protein array analysis revealed that the inhibitory activity of siIL-32 primarily targeted Th1 and proinflammatory cytokines and chemokines, e.g., MIP-1/β. Unexpectedly, HIV-1 production (as measured by p24) increased 4-fold in these same PBMC when endogenous IL-32 was reduced. Because IFN- was lower in siIL-32-treated PBMC, we blocked IFN- bioactivity, which enhanced the augmentation of p24 by siIL-32. Furthermore, siIL-32 reduced the natural ligands of the HIV-1 coreceptors CCR5 (MIP-1/β and RANTES) and CXCR4 (SDF-1). Inhibition of endogenous IL-32 in U1 macrophages also increased HIV-1. When rhIL-32 was added to these cells, p24 levels fell by 72%; however, in the same cultures IFN- increased 4-fold. Blockade of IFN-/β bioactivity in IL-32-stimulated U1 cells revealed that IFN- conveys the anti-HIV-1 effect of rhIL-32. In summary, depletion of endogenous IL-32 reduced the levels of Th1 and proinflammatory cytokines but paradoxically increased p24, proposing IL-32 as a natural inhibitor of HIV-1.

First presented at the 15th Annual Meeting of The International Cytokine Society, October 26–30, 2007, San Francisco, CA and published in Abstract form in Cytokine, Vol. 39, Issue 1, July 2007, page 30.

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 Grant AI 15614 and by the Center for AIDS Research of the University of Colorado Health Sciences Center (both to C.A.D.). M.F.N. is supported in part by the Deutsche Forschungsgemeinschaft (No 747/1-1).

² Address correspondence and reprint requests to Dr. Charles A. Dinarello, Department of Medicine, Division of Infectious Diseases, B168, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262. E-mail address: cdinarello{at}mac.com

³ Abbreviations used in this paper: P/S, penicillin/streptomycin; ECL, electrochemiluminescence; LDH, lactate dehydrogenase; RLU, relative light unit; siIL-32, siRNA to IL-32; siRNA, small interfering RNA; TCID₅₀, 50% tissue culture infective dose.

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