Abstract
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-alpha and IL-6. Using peripheral blood (PB) monocytes, RANTES decreased LPS-induced IL-6 transcriptionally, whereas TNF-alpha 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-alpha. 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-alpha. In conclusion, the results of this study suggest that RANTES down-regulates TLR4 ligation-induced IL-6 and TNF-alpha 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.
Highlights
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To determine the effect of RANTES on LPS-induced cytokine production, human peripheral blood (PB) monocytes were incubated with PBS or RANTES (10 ng/ml) for 24 h
The LPS-induced expression of IL-6 and TNF-␣ mRNA peaked at 4 h, and RANTES suppressed ( p Ͻ 0.01) IL-6 mRNA levels at each time point examined (Fig. 1C)
Summary
RA, rheumatoid arthritis; PB, peripheral blood; siRNA, short-interfering RNA; Met-RANTES, methionylated RANTES; MK2, MAPK-activated protein kinase. Collagen-induced arthritis is increased in CCR2-null mice compared with wild-type controls [9] These findings suggest that chemokine inhibition may differentially affect inflammatory responses in rodent models of RA depending on the time of intervention, suggesting a potential biological role for chemokines beyond their effects on leukocyte trafficking. Supporting this possibility, RANTES and MCP-1/CCL2 induce RA synovial tissue fibroblasts to produce IL-6 and IL-8 [10]. RANTES may be capable of modulating the inflammatory response via the induction of IL-10 in a cell type-specific manner These effects may be critical for understanding the therapeutic consequences of chemokine inhibition for chronic inflammation. Commercial kits for human IL-6, TNF-␣, and IL-10 (DuoSet ELISA; R&D Systems), were used for cytokine quantification as per the manufacturer’s instructions
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