Increased numbers of mast cells are found in the synovial tissues and fluids of patients with rheumatoid arthritis, and at sites of cartilage erosion. Mast cell activation has been reported for a significant proportion of rheumatoid specimens. Because the mast cell contains potent mediators, including histamine, its potential contributions to the processes of inflammation and matrix degradation have recently become evident; thereafter, we investigated the potential protective effect of histamine deficiency against aggrecan-induced arthritis. To study the role of histamine in rheumatoid arthritis we investigated cartilage proteoglycan (aggrecan)-induced arthritis in histidine decarboxylase knockout (HDC-KO) mice, with complete lack of endogenously produced histamine. Aggrecan-induced arthritis was similar in HDC-KO and wild-type (WT) mice. Arthritis was even more severe in HDC-KO mice than in the WT animals 10 weeks following the immunization with aggrecan (arthritis score 1.2 ± 1.5 and 0 ± 0, respectively; P = 0.01). At later time points, arthritis scores were similar in both HDC-KO and WT mice. Since T-lymphocyte dysfunction has an important role in the pathogenesis of rheumatoid arthritis, next we investigated T-cell signal transduction and cytokine production in HDC-KO and WT mice. In the absence of histamine, elevated INFγ mRNA and protein levels of splenocytes (P < 0.001 and P = 0.001, respectively) were associated with a markedly increased (2.5-fold, P = 0.0009) nitric oxide (NO) production, compared with WT animals. Furthermore, histamine treatment decreased the NO production of splenocytes from both WT and HDC-KO mice (P = 0.001 and P = 0.0004, respectively). NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate-diethylenetriamine (NOC-18) elicited IFNγ production (P = 0.0002), suggesting the role of NO in regulating IFNγ synthesis. The cytoplasmic Ca2+ concentration of unstimulated T cells and the T-cell activation-induced Ca2+ signal were increased in T cells from the HDC-KO mice (P = 0.02 and P = 0.04, respectively), while the T-cell activation-induced CD3 internalization was similar in both HDC-KO and WT animals. Our present data indicate that histamine deficiency does not protect against aggrecan-induced arthritis. The Th1 cytokine pattern and increased NO production may both contribute to the sensitivity of HDC-KO mice to aggrecan-induced arthritis. Furthermore, our data indicate that histamine, in addition to its direct effects on T-lymphocyte function, regulates cytokine production and T-cell signal transduction through regulating NO production.
This work was supported by grants OTKA F 61030 and OTKA T 046468.