Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation.
The ST2 gene produces a soluble secreted form and a transmembrane form, referred to as soluble ST2 and ST2L, respectively. A recent study has reported that interleukin (IL)-33 is a specific ligand of ST2L and induces production of T helper type 2 (Th2) cytokines. Although soluble ST2 is highly produced in sera of asthmatic patients and plays a critical role for production of Th2 cytokines, the function of soluble ST2 in relation to IL-33 signaling remains unclear. Here we show antagonistic effects of soluble ST2 on IL-33 signaling using a murine thymoma EL-4 cells stably expressing ST2L and a murine model of asthma. Soluble ST2 directly bound to IL-33 and suppressed activation of NF-kappaB in EL-4 cells stably expressing ST2L, suggesting that the complex of soluble ST2 and IL-33 fails to bind to ST2L. In a murine model of asthma, pretreatment with soluble ST2 reduced production of IL-4, IL-5, and IL-13 from IL-33-stimulated splenocytes. These results indicate that soluble ST2 acts as a negative regulator of Th2 cytokine production by the IL-33 signaling. Our study provides a molecular mechanism wherein soluble ST2 modulates the biological activity of IL-33 in allergic airway inflammation.
Hayakawa
Hiroko
H
Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
Hayakawa
Morisada
M
Kume
Akihiro
A
Tominaga
Shin-ichi
S
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology*; D018123:Receptors, Interleukin; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
D016207:Cytokines; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D008565:Membrane Proteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin