Recombinant ST2 boosts hepatic Th2 response in vivo.
Excessive scarring or fibrosis is a common feature of a wide spectrum of diseases characterized by an exaggerated Th2 response. The TLR/IL-1 receptor (IL-1R)-related protein ST2 is expressed in a membrane-bound form selectively by Th2 cells and was shown to be indispensable for some in vivo Th2 responses. ST2 was also found to block TLR signaling. We addressed the impact of the ST2 pathway on fibrogenesis using a mouse model of hepatic injury and fibrosis induced by carbon tetrachloride (CCl(4)). We showed that cytokine production by intrahepatic lymphocytes from CCl(4)-injured liver is abrogated in the absence of TLR-4. Interfering with the ST2 pathway using an ST2-Fc fusion protein accelerated and enhanced hepatic fibrosis, paralleled by the increasing ex vivo secretion of Th2 cytokines IL-4, -5, -10, and -13 by intrahepatic lymphocytes of ST2-Fc-treated, CCl(4)-gavaged mice. Absence of IL-4/13 signaling in IL-4Ralpha-deficient mice obliterated this ST2-Fc effect on fibrogenesis. Moreover, depletion of CD4(+) T cells abrogated ST2-Fc-enhanced Th2 cytokines and accelerated fibrosis. Thus, ST2-Fc caused overproduction of Th2 cytokines by intrahepatic CD4(+) T cells, possibly by modifying TLR-4 signaling in injured liver. This ST2-Fc-driven Th2 response exacerbated CCl(4)-induced hepatic fibrosis.
Amatucci
Aldo
A
Biogen Idec, Cambridge, Massachusetts, USA. aldo.amatucci@biogenidec.com
Novobrantseva
Tatiana
T
Gilbride
Kevin
K
Brickelmaier
Margot
M
Hochman
Paula
P
Ibraghimov
Alexander
A
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002251:Carbon Tetrachloride; D016207:Cytokines / Q000096:biosynthesis*; D005355:Fibrosis / Q000139:chemically induced / Q000209:etiology* / Q000276:immunology; D007141:Immunoglobulin Fc Fragments; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008107:Liver Diseases / Q000276:immunology* / Q000517:prevention & control; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; D018418:Th2 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D016207:Cytokines; C486189:Il1rl1 protein, mouse; D007141:Immunoglobulin Fc Fragments; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008565:Membrane Proteins; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002251:Carbon Tetrachloride