Green tea extract inhibits chemokine production, but up-regulates chemokine receptor expression, in rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis

H Marotte,J H Ruth,P L Campbell,S Ahmed,A E Koch

doi:10.1093/rheumatology/kep397

H Marotte, J H Ruth + Show 3 more

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https://doi.org/10.1093/rheumatology/kep397

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Journal: Rheumatology	Publication Date: Dec 23, 2009
Citations: 57	License type: cc-by

Affiliation: University of Michigan–Ann Arbor

Abstract

Evaluation of the efficacy of green tea extract (GTE) in regulating chemokine production and chemokine receptor expression in human RA synovial fibroblasts and rat adjuvant-induced arthritis (AIA). Fibroblasts isolated from human RA synovium were used in the study. Regulated upon activation normal T cell expressed and secreted (RANTES)/CCL5, monocyte chemoattractant protein (MCP)-1/CCL2, growth-regulated oncogene (GRO)alpha/CXCL1 and IL-8/CXCL8 production was measured by ELISA. Western blotting was used to study the phosphorylation of protein kinase C (PKC)delta and c-Jun N-terminal kinases (JNK). Chemokine and chemokine receptor expression was determined by quantitative RT-PCR. The benefit of GTE administration in rat AIA was determined. GTE (2.5-40 microg/ml) inhibited IL-1beta-induced MCP-1/CCL2 (10 ng/ml), RANTES/CCL5, GROalpha/CXCL1 and IL-8/CXCL8 production in human RA synovial fibroblasts (P < 0.05). However, GTE inhibited MCP-1/CCL2 and GROalpha/CXCL1 mRNA synthesis in RA synovial fibroblasts. Furthermore, GTE also inhibited IL-1beta-induced phosphorylation of PKCdelta, the signalling pathway mediating IL-1beta-induced chemokine production. Interestingly, GTE preincubation enhanced constitutive and IL-1beta-induced CCR1, CCR2b, CCR5, CXCR1 and CXCR2 receptor expression. GTE administration (200 mg/kg/day p.o.) modestly ameliorated rat AIA, which was accompanied by a decrease in MCP-1/CCL2 and GROalpha/CXCL1 levels and enhanced CCR-1, -2, -5 and CXCR1 receptor expression in the joints of GTE administered rats. Chemokine receptor overexpression with reduced chemokine production by GTE may be one potential mechanism to limit the overall inflammation and joint destruction in RA.

Highlights

RA is a chronic inflammatory disease leading to joint destruction mediated in part by the migration of inflammatory cells into the synovial tissue [1]
green tea extract (GTE) administration (200 mg/kg/day p.o.) modestly ameliorated rat adjuvant-induced arthritis (AIA), which was accompanied by a decrease in monocyte chemoattractant protein (MCP)-1/CCL2 and growth-regulated oncogene a (GROa)/CXCL1 levels and enhanced CCR-1, -2, -5 and CXCR1 receptor expression in the joints of GTE administered rats
Stimulation of RA synovial fibroblasts with IL-1b (10 ng/ml) for 24 h resulted in a 5, 21, 21- and 96-fold induction of monocyte chemoattractant protein 1 (MCP-1)/CCL2, RANTES/CCL5, GROa/CXCL2 and IL-8/CXCL8, production, respectively, as compared with untreated controls (P < 0.05; n 5 4)

Summary

Introduction

RA is a chronic inflammatory disease leading to joint destruction mediated in part by the migration of inflammatory cells into the synovial tissue [1]. CC and CXC chemokines are well-established regulators of gene transcription, cell proliferation and leucocyte trafficking to normal and inflamed tissues [6, 7]. Chemokines such as monocyte chemoattractant protein 1 (MCP-1)/CCL2, regulated upon activation normal T cell expressed and secreted (RANTES)/CCL5, growth-regulated oncogene a (GROa)/CXCL1 and IL-8/CXCL8 are potent chemotactic agents that are constitutively produced by RA synovial fibroblasts and further up-regulated upon cytokine stimulation [8]. Chemokines have been associated with the regulation of leucocyte trafficking to normal and inflamed tissues [11, 12]. In addition to leucocytes, the other non-haematopoietic cell types, including endothelial cells, fibroblasts and several tumour lineage cells, express chemokine receptors [10,11,12]

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