The essential role of single Ig IL-1 receptor-related molecule/Toll IL-1R8 in regulation of Th2 immune response.
A novel cytokine IL-33, an IL-1 family member, signals via ST2 receptor and promotes Th2 responses, through the activation of NF-kappaB and MAP kinases. Previous studies reported that single Ig IL-1R-related molecule (SIGIRR)/Toll IL-1R8 acts as negative regulator for TLR-IL-1R-mediated signaling. We now found that SIGIRR formed a complex with ST2 upon IL-33 stimulation and specifically inhibited IL-33/ST2-mediated signaling in cell culture model. Furthermore, IL-33-induced Th2 response was enhanced in SIGIRR-deficient mice compared with that in wild-type control mice, suggesting a negative regulatory role of SIGIRR in IL-33/ST2 signaling in vivo. Similar to ST2, SIGIRR was highly expressed in in vitro polarized Th2 cells, but not Th1 cells. SIGIRR-deficient Th2 cells produce higher levels of Th2 cytokines, including IL-5, IL-4, and IL-13, than that in wild-type cells. Moreover, SIGIRR-deficient mice developed stronger Th2 immune response in OVA-challenged asthma model. Taken together, our results suggest that SIGIRR plays an important role in the regulation of Th2 response in vivo, possibly through its impact on IL-33-ST2-mediated signaling.
Bulek
Katarzyna
K
Immunology Department, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Swaidani
Shadi
S
Qin
Jinzhong
J
Lu
Yi
Y
Gulen
Muhammet F
MF
Herjan
Tomasz
T
Min
Booki
B
Kastelein
Robert A
RA
Aronica
Mark
M
Kosz-Vnenchak
Magdalena
M
Li
Xiaoxia
X
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D008565:Membrane Proteins; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C484529:SIGIRR protein, mouse