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The Role of IFN- and Nitric Oxide in the Release of HMGB1 by RAW 264.7 Cells Stimulated with Polyinosinic-Polycytidylic Acid or Lipopolysaccharide¹

Weiwen Jiang^* and David S. Pisetsky^2,*,

^* Division of Rheumatology and Immunology, Department of Medicine, Duke University, Durham, NC 27710; and Medical Research Service, Durham Veterans Affairs Medical Center, Durham, NC 27705

High mobility group protein 1 (HMGB1) is a nonhistone nuclear protein with a dual function. Inside the cell, HMGB1 binds to DNA and modulates a variety of processes, including transcription. Outside the cell, HMGB1 displays cytokine activity and can promote inflammation, serving as a mediator in models of shock and arthritis. In in vitro studies, proinflammatory molecules such as LPS, lipoteichoic acid, dsRNA, TNF-, and IFN- can induce HMGB1 release from macrophages. To define further the release process, we investigated the role of the downstream mediators, NO and IFN-, in the release of HMGB1 from RAW 264.7 macrophage cells stimulated with LPS or polyinosinic-polycytidylic acid (poly(I:C)). In these experiments, 1400W, an inhibitor of NO production by the inducible NO synthase, reduced HMGB1 release stimulated by LPS, but not poly(I:C), whereas neutralizing IFN- prevented HMGB1 release induced by poly(I:C), but not LPS. The addition of an NO donor and rIFN- to RAW 264.7 cells caused HMGB1 release. Furthermore, inhibition of JNK activation attenuated HMGB1 release induced by either LPS or poly(I:C). Analysis of bone marrow-derived macrophages stimulated by LPS or poly(I:C) showed patterns of HMGB1 release similar to those of RAW 264.7 cells. Together, these experiments indicate that, although both LPS and poly(I:C) induce HMGB1 release from RAW 264.7 cells and murine macrophages, the response is differentially dependent on NO and IFN-.

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 is supported by Veterans Affairs Medical Research Service, National Institutes of Health Grant AI44808, and a grant from the Lupus Research Institute. W.J. is supported by National Institutes of Health Training Grant T32 EB01630.

² Address correspondence and reprint requests to Dr. David S. Pisetsky, 151G Durham Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC 27705. E-mail address: piset001{at}mc.duke.edu

³ Abbreviations used in this paper: HMGB1, high mobility group protein 1; BMMC, bone marrow-derived macrophage; iNOS, inducible NO synthase; L-NIL, L-N⁶-iminoethyl-lysine; MCMV, mouse CMV; pDC, plasmacytoid dendritic cell; poly(I:C), polyinosinic-polycytidylic acid; siRNA, small inhibitory RNA; TRIF, Toll/IL-1R domain-containing adaptor inducing IFN-.

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