Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells.
Interleukin (IL)-18 induces interferon (IFN)-gamma synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rbeta2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R-derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin-T cell antigen receptor-alphabeta transgenic mice (D011.10). Anti-IL-18R antibody inhibited IL-18- induced IFN-gamma production by Th1 clones in vitro. In vivo, anti-IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-gamma and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.
Xu
D
D
Department of Immunology, University of Glasgow, Glasgow G11 6NT, United Kingdom.
Chan
W L
WL
Leung
B P
BP
Hunter
D
D
Schulz
K
K
Carter
R W
RW
McInnes
I B
IB
Robinson
J H
JH
Liew
F Y
FY
D000818:Animals; D002460:Cell Line; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D053727:Interleukin-18 Receptor alpha Subunit; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D018123:Receptors, Interleukin / Q000502:physiology*; D053724:Receptors, Interleukin-18; D012772:Shock, Septic / Q000517:prevention & control; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*
C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D008070:Lipopolysaccharides; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma