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Expression of Interleukin 12 Receptor (IL-12R) and IL-18R on CD4+ T Cells from Patients with Rheumatoid Arthritis
TETSUSHI AITA, MASAHIRO YAMAMURA, MASANORI KAWASHIMA, AKIRA OKAMOTO, MITSUHIRO IWAHASHI, JIRO YAMANA, and HIROFUMI MAKINO
ABSTRACT. Objective. Interleukin 12 (IL-12) and IL-18 synergistically induce interferon-γ (IFN-γ) production by T cell infiltrates in rheumatoid arthritis (RA). To investigate this synergism, we examined the expression and regulation of IL-12 receptor (IL-12R) and IL-18R on peripheral blood (PB) and synovial tissue (ST) CD4+ T cells from patients with RA. Methods. The mRNA and cell surface expression of IL-12R and IL-18R in CD4+ T cells were determined by reverse transcriptase-polymerase chain reaction and flow cytometry, respectively. IFN-γ and IL-4 production by CD4+ T cells stimulated with phorbol myristate acetate (PMA) and calcium ionophore A23187 was measured by intracellular cytokine staining and flow cytometry. Results. Despite the negligible expression of IL-12R on fresh cells, PB CD4+ T cells from RA patients expressed higher levels of both IL-12Rß1 and ß2 subunits after stimulation with anti-CD3 antibody (Ab) than the cells of healthy controls. ST CD4+ T cells contained mRNA transcripts encoding IL-12Rß1 and ß2, and expressed detectable levels of these 2 subunits on the cell surface. Their IL-12R expression was markedly augmented by costimulation with anti-CD3 Ab and IL-18. In contrast, IL-18Rα was expressed on freshly isolated PB CD4+ T cells from RA patients and controls, and the level of expression was higher in RA. IL-18Rα+ CD4+ T cells were further increased in the ST lesion, where IL-18Rß mRNA was constitutively detected. IL-12Rß1 and ß2 were induced mainly on IL-18Rα+ CD4+ T cells after anti-CD3 Ab stimulation. PMA and A23187-activated ST CD4+ T cells mostly expressed IL-18Rα and produced high levels of IFN-γ. Conclusion. These results indicate that IL-18R-expressing CD4+ T cells are accumulated in the ST of patients with RA, where the functional IL-12R is locally induced by stimuli such as CD3 activation and IL-18. Activation of both cytokine receptors may be necessary for the IFN-γ-dominant cytokine response. (J Rheumatol 2004;31:448-56) Key Indexing Terms:
CD4+ T CELLS From the Department of Medicine and Clinical Science, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan. Supported by grants-in-aid (12670426/14570413) from the Ministry of Education, Science, Culture, and Technology of Japan. T. Aita, MD; M. Yamamura, MD, PhD; M. Kawashima, MD, PhD; A. Okamoto, MD; M. Iwahashi, MD; J. Yamana, MD; H. Makino, MD, PhD. Address reprint requests to Dr. M. Yamamura, Department of Medicine and Clinical Science, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Submitted April 23, 2003; revision accepted July 25, 2003. |