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Rheumatology 2002; 41: 883-891
© 2002 British Society for Rheumatology

Original Papers

Tumour necrosis factor {alpha} stimulates nitric oxide production more potently than interleukin-1ß in porcine articular chondrocytes

N. J. Goodstone and T. E. Hardingham

The Wellcome Trust Centre for Cell Matrix Research, School of Biological Sciences, The University of Manchester, Manchester M139PT, UK

Objective. To compare the time- and concentration-dependent effects of tumour necrosis factor {alpha} (TNF-{alpha}) and interleukin 1ß (IL-1ß) on the induction of nitric oxide synthase (NOS), the production of nitric oxide (NO) and the expression of aggrecan and hyaluronan (HA) in chondrocytes.

Methods. Primary porcine articular chondrocytes were treated with recombinant human (rh) TNF-{alpha} or rhIL-1ß for up to 72 h. Culture supernatants were assayed for NO production. Synthesis of HA and aggrecan was determined by radiolabelling cultures with [3H]glucosamine and/or [35S]sulphate. Total RNA was isolated and the time courses of changes in gene expression of inducible NOS and HA synthase-2 were investigated by reverse transcriptase–polymerase chain reaction.

Results. rhTNF-{alpha} stimulated more NO production than rhIL-1ß. It was also active at lower concentrations; rhTNF-{alpha} at 0.006 pM (100 pg/ml) was equivalent to rhIL-1ß at 0.29 pM (5000 pg/ml). The time course of induction was transient and slower at low concentrations. Contrary to previous reports, rhTNF-{alpha} and rhIL-1ß were of similar potency in the inhibition of aggrecan synthesis. In contrast, both cytokines stimulated HA synthesis, and this was correlated with the transient induction of HA synthase-2. An inhibitor of inducible NOS relieved the inhibition of aggrecan synthesis caused by both cytokines at low concentrations, but it showed little effect on HA synthesis.

Conclusion. At low concentrations, rhTNF-{alpha} was 50 times more potent than rhIL-1ß in stimulating NO production by chondrocytes and it was of similar potency in inhibiting aggrecan synthesis and in stimulating HA synthesis. Inhibition of inducible NOS activity relieved some of the effects on aggrecan synthesis, showing that part of the action of TNF-{alpha} is mediated through NO. HA synthesis was not affected.

Correspondence to: N. J. Goodstone, The Arthritis Research Centre, The Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire SY107AG, UK.


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