Crucial role of interleukin‐10/interleukin‐12 balance in the regulation of the type 2 T helper cytokine response in reactive arthritis

Abstract

Objective. To investigate whether a predominant type 1 T helper (Thl) or Th2 cytokine pattern is present in the joints of patients with reactive arthritis (ReA), and whether the cytokine pattern can be modulated by cytokines or anticytokines. Methods. Eleven patients with ReA following infection with either Chlamydia trachomatis, Yersinia enterocolitica, or Salmonella enteritidis were investigated for the presence of Th1/Th2 cytokines in the joints. Release of the bacteria‐specific cytokines interferon‐γ (IFNγ), tumor necrosis factor α (TNFα), interleukin‐10 (IL‐10), and IL‐4 was measured in synovial fluid mononuclear cells (SFMC) using enzyme‐linked immunosorbent assay and polymerase chain reaction. In the synovial membrane, secretion of IFNγ and IL‐4 was determined by immunohistologic analysis. Cytokine regulation was studied by adding cytokines and anticytokines to the cultures. Results. Upon stimulation with specific bacteria, SFMC secreted low amounts of IFNγ and TNFα, but high amounts of IL‐10. IL‐10 was responsible for the suppression of IFNγ and TNFα, as judged by the effect of adding either anti‐IL‐10 antibodies or exogenous IL‐10 to these cultures. The addition of neutralizing anti‐IL‐12 to the cultures completely abolished the effects of anti‐IL‐10, suggesting that inhibition of the Th1‐like cytokines by IL‐10 is mediated through suppression of IL‐12 synthesis. Exogenous IL‐12 clearly enhanced IFNγ and TNFα secretion. In the synovial membrane, a higher number of cells were positive for the Th2 cytokine IL‐4, compared with the amount of IFNγ‐secreting cells. Conclusion. These data indicate that a Th2 cytokine pattern predominates in the joints of patients with ReA. Since Thl cytokines are necessary for the elimination of ReA‐associated bacteria, Th2 cytokines might contribute to bacterial persistence in the joint. Therefore, the IL‐10/IL‐12 balance appears to be crucial for regulation of the cytokine pattern in the joints of patients with ReA.

Early cytokine profiles in the joint define pathogen clearance and severity of arthritis in Chlamydia‐induced arthritis in rats

“…Mononuclear cells in synovial fluid have been shown to express high levels of IL-4 and IL-10. Consistent with culture data, more IL-4-expressing cells than IFN␥-expressing cells were observed in the synovial membrane (35).…”

“…In ReA, failure of effective bacterial elimination at the initiation of the disease may be attributable to a relative lack of Th1 cytokine production. Several studies have demon- 504 INMAN AND CHIU strated a relative decrease in Th1 cytokines in peripheral blood and synovium of patients with ReA (35,37). In a study of 11 patients with ReA, it was shown that stimulation of synovial fluid mononuclear cells resulted in low levels of IFN␥ and TNF␣ but high amounts of IL-10 (35).…”

Multispecific CD4+ T Cell Response to a Single 12-mer Epitope of the Immunodominant Heat-Shock Protein 60 ofYersinia enterocoliticainYersinia-Triggered Reactive Arthritis: Overlap with the B27-Restricted CD8 Epitope, Functional Properties, and Epitope Presentation by Multiple DR Alleles

“…A Th1 response is crucial for successfully fighting microbes such as Yersinia and Chlamydia, and their elimination is inhibited by IL-10 (9 -11). We have previously reported that a relative high amount of IL-4 and IL-10 and/or a low secretion of IFN-␥ and TNF-␣ occurs in the joint (5,6) or peripheral blood (42) of ReA patients, suggesting that such an ineffective Th1 response contributes to bacterial persistence. Therefore, the analysis of the cytokine secretion pattern of the TCCs upon stimulation with the immunodominant epitope was of great interest.…”

“…The presence of bacterial Ag (2,3) or DNA (4) in the joint suggests that local Ag may drive the immune response. The recent description of a Th2-cytokine secretion pattern in ReA (5)(6)(7)(8) suggests that an ineffective Th1 response may contribute to bacterial persistence in vivo, because Th1 cytokines such as IFN-␥ and TNF-␣ are crucial for the elimination of both Chlamydia (9,10) and Yersinia (11).…”

“…Culture supernatants were harvested after 48 h of T cell stimulation for determination of Ag-induced cytokine secretion, and the concentration of cytokines in the supernatant was measured as described previously (5,22). Briefly, levels of IFN-␥, TNF-␣, IL-10, and IL-4 were analyzed by sandwich ELISA using purified anti-cytokine mAb (capture) and biotinylated anti-cytokine mAbs (detecting) (PharMingen, San Diego, CA), with a detection level of 6 pg/ml for IL-4 and 20 pg/ml for the other three cytokines.…”