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Lab Invest. 2002 Oct;82(10):1297-304.

Involvement of CXC chemokine growth-related oncogene-alpha in monosodium urate crystal-induced arthritis in rabbits.

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Department of Pathology, Kumamoto University School of Medicine, Kumamoto, Japan.


Accumulation of neutrophils is a prominent feature of gouty arthritis in which CXC chemokines may play a role. Recently, we have shown that IL-8 (CXCL8) contributes to neutrophil influx in a rabbit model of gouty arthritis. Here, we demonstrate that growth-related oncogene-alpha (GROalpha) (CXCL1), a prototype of CXC chemokine, is also involved in this process. GROalpha level in the joints peaked at 2 hours after intra-articular injection of monosodium urate crystals, at a time before the neutrophil influx reached the maximal level (9 hours). Once decreased, the level increased and reached the second peak at 9 hours. The kinetics was comparable to that of IL-8. Administration of anti-GROalpha mAb attenuated the neutrophil influx at the same level as did the anti-IL-8 IgG, and combination of these antibodies enhanced the inhibition, resulting in a 33% reduction. Interaction of GROalpha with TNFalpha, IL-1beta, and IL-8 was next investigated by injecting antibodies or receptor antagonist with monosodium urate crystals. Administration of anti-TNFalpha mAb did not alter GROalpha level at 2 hours, but inhibited the levels 9 hours after the injection. Treatment with either IL-1 receptor antagonist or anti-IL-8 IgG resulted in decreased levels of GROalpha at 2 and 9 hours. Neutralization of GROalpha with anti-GROalpha mAb did not alter TNFalpha, IL-1beta, and IL-8 levels at their peak (2 hours), but decreased the second peak of IL-1beta (9 hours) and IL-8 (12 hours). These results provide evidence that GROalpha as well as IL-8 are involved ad eundem in the neutrophil infiltration in this model. IL-1 and IL-8, but not TNFalpha, are responsible in part for the initial phase of GROalpha, whereas these cytokines induce GROalpha in a late phase. GROalpha does not seem to initiate TNFalpha, IL-1beta, and IL-8 in an early phase, but induces IL-1beta and IL-8 in a late phase.

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