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RANTES Modulates TLR4-Induced Cytokine Secretion in Human Peripheral Blood Monocytes¹

Shiva Shahrara^2,*, Christy C. Park^*, Vladislav Temkin^*, Jared W. Jarvis^*, Michael V. Volin and Richard M. Pope^*

^* Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611; and Department of Microbiology and Immunology, Midwestern University, Chicago College of Osteopathic Medicine, Downers Grove, IL 60515

Monocytes are the key regulators of joint inflammation and destruction in rheumatoid arthritis; hence, suppression of their recruitment into the joint may be therapeutically beneficial. Chemokines, including RANTES, are highly expressed in the joints of patient with rheumatoid arthritis, and they promote leukocyte trafficking into the synovial tissue. Because endogenous TLR4 ligands are expressed in the rheumatoid joint, the TLR4 ligand LPS was used to characterize the effects of RANTES on the TLR4-mediated induction of TNF- and IL-6. Using peripheral blood (PB) monocytes, RANTES decreased LPS-induced IL-6 transcriptionally, whereas TNF- was suppressed at the posttranscriptional level. RANTES signaled through p38 MAPK, and this signaling was further enhanced by LPS stimulation in PB monocytes, resulting in the earlier and increased secretion of IL-10. Inhibition of p38 by short-interfering RNA or a chemical inhibitor, as well as neutralization of IL-10, reversed the RANTES-mediated suppression of LPS-induced IL-6 and TNF-. Further, when rheumatoid arthritis synovial fluid was added to PB monocytes, the neutralization of RANTES in fluid reduced the LPS-induced IL-10 and increased TNF-. In conclusion, the results of this study suggest that RANTES down-regulates TLR4 ligation-induced IL-6 and TNF- secretion by enhancing IL-10 production in PB monocytes. These observations suggest that the therapeutic neutralization of RANTES, in addition to decreasing the trafficking of leukocytes, may have a proinflammatory effect at the site of established chronic inflammation.

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 Health Grants AR049353 (to S.S.) and AR049217 and AR048269 (to R.M.P.).

² Address correspondence and reprint requests to Dr. Shiva Shahrara, Northwestern University, Feinberg School of Medicine, Department of Medicine, Section of Rheumatology, McGaw Pavilion, 240 East Huron, Suite 2220, Chicago, IL 60611. E-mail address: s-shahrara{at}northwestern.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; PB, peripheral blood; siRNA, short-interfering RNA; Met-RANTES, methionylated RANTES; MK2, MAPK-activated protein kinase.

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