Expression of interleukin 12 receptor (IL-12R) and IL-18R on CD4+ T cells from patients with rheumatoid arthritis.
OBJECTIVE
Interleukin 12 (IL-12) and IL-18 synergistically induce interferon-gamma (IFN-gamma) 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-gamma 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-12Rbeta1 and beta2 subunits after stimulation with anti-CD3 antibody (Ab) than the cells of healthy controls. ST CD4+ T cells contained mRNA transcripts encoding IL-12Rbeta1 and beta2, 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-18Ralpha was expressed on freshly isolated PB CD4+ T cells from RA patients and controls, and the level of expression was higher in RA. IL-18Ralpha+ CD4+ T cells were further increased in the ST lesion, where IL-18Rbeta mRNA was constitutively detected. IL-12Rbeta1 and beta2 were induced mainly on IL-18Ralpha+ CD4+ T cells after anti-CD3 Ab stimulation. PMA and A23187-activated ST CD4+ T cells mostly expressed IL-18Ralpha and produced high levels of IFN-gamma.


CONCLUSIONS
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-gamma-dominant cytokine response.
Department of Medicine and Clinical Science, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan.
Tetsushi
T
Aita
Masahiro
M
Yamamura
Masanori
M
Kawashima
Akira
A
Okamoto
Mitsuhiro
M
Iwahashi
Jiro
J
Yamana
Hirofumi
H
Makino
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D053727:Interleukin-18 Receptor alpha Subunit; D008297:Male; D008875:Middle Aged; D018123:Receptors, Interleukin / Q000032:analysis / Q000096:biosynthesis*; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D013583:Synovial Membrane / Q000737:chemistry; D018417:Th1 Cells / Q000276:immunology
C508439:IL12RB2 protein, human; C508572:IL18R1 protein, human; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D007371:Interferon-gamma