Abstract
IntroductionOur previous studies showed that arthritic Lewis (LEW) rats produced the highest levels of tumour necrosis factor (TNF)α in the recovery phase of adjuvant arthritis (AA), suggesting a correlation between high TNFα levels and reduced severity of arthritis. To further explore this correlation, we compared the TNFα secretion profile of the AA-resistant Wistar Kyoto (WKY) rats with that of LEW rats, determined the effect of exogenous TNFα on the course of AA in LEW rats, and examined various mechanisms involved in TNFα-induced disease modulation.MethodsA cohort each of LEW and WKY rats was immunised subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra (Mtb). At different time points thereafter, subgroups of rats were killed and their draining lymph node cells were tested for cytokine production. Another group of LEW rats was injected with TNFα intraperitoneally daily for a total of 10 injections, 3 before and 6 after Mtb challenge, and then observed for signs of AA. In parallel, TNFα-treated rats were examined for changes in other cytokines, in CD4+CD25+ T cell frequency, and in indoleamine 2,3-dioxygenase (IDO) mRNA expression levels.ResultsLEW rats displayed a TNFα secretion profile that was opposite to that of the WKY rats. Furthermore, TNFα treatment significantly downmodulated the severity of AA in LEW rats, and decreased the interferon (IFN)-γ secretion in response to the pathogenic determinant of the disease-related antigen. No significant alterations were observed in other parameters tested.ConclusionThe role of endogenous TNFα in the induction and propagation of arthritis is well established. However, exogenous TNFα can downmodulate the course of AA, displaying an immunoregulatory functional attribute of this cytokine.
Highlights
Our previous studies showed that arthritic Lewis (LEW) rats produced the highest levels of tumour necrosis factor (TNF)α in the recovery phase of adjuvant arthritis (AA), suggesting a correlation between high tumour necrosis factor α (TNFα) levels and reduced severity of arthritis
Arthritis Research & Therapy Vol 10 No 1 Kim et al Our results show that the AA-susceptible Lewis (LEW) rats given an arthritogenic stimulus showed the highest levels of TNFα in the recovery phase of AA, displaying a TNFα profile opposite to that of the AA-resistant Wistar Kyoto (WKY) rats
Arthritic LEW rats show highest levels of TNFα at the recovery phase of AA, whereas AA-resistant WKY rats exhibit an opposite profile The results of ex vivo TNFα secretion showed that there was a gradual increase in levels along with the progression of AA in LEW rats with the highest level observed during Rec phase, while an opposite pattern was observed in WKY rats
Summary
Our previous studies showed that arthritic Lewis (LEW) rats produced the highest levels of tumour necrosis factor (TNF)α in the recovery phase of adjuvant arthritis (AA), suggesting a correlation between high TNFα levels and reduced severity of arthritis. In the course of our preliminary studies in the rat adjuvantinduced arthritis (AA) model of human RA [8,9,10,11,12,13], we observed that the levels of TNFα produced by the arthritogenic epitope of mycobacterial heat-shock protein 65 (Bhsp65) [10,11,12,14] were highest in the recovery phase of the disease compared to that at the onset or the peak phase of AA This unexpected correlation has formed the basis of subsequent experiments described in the present work
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