ST2 is not required for the profibrotic effect of precursor IL-33 in the lungs 2689

Abstract Description The mature IL-33 (MIL33) cytokine acting through its specific cell-surface receptor, ST2, contributes to disease pathogenesis including lung scarring, a.k.a. pulmonary fibrosis (PF). In PF, deletion or depletion of either MIL33 or ST2 ameliorates the severity of scarring. Surprisingly, data from us and others suggest that elevated IL-33 might mediate PF without engaging ST2. We utilized mice that were germline-deficient of both IL-33 and ST2 genes. Adenovirus (AdV)-mediated gene delivery of either MIL33 or full-length IL-33 (FLIL33) precursor to mouse lungs was achieved through intratracheal (IT) instillation. In the absence of ST2, which is critically required for mediating all functional effects of MIL33, the regulation by MIL33, either AdV-delivered or endogenous, is blocked. In further absence of endogenous IL-33, any potential regulation by natural FLIL33 or MIL33 is excluded. The only effects expected in this model are those from overexpressed FLIL33. Seven days after AdV instillations, mice were challenged with IT bleomycin (BLM) to induce PF. After an additional 14 days, the total lung collagen content was measured. Compared with the AdV-NULL control not expressing a cytokine, mice overexpressing FLIL33 but not MIL33 had a greater increase in the levels of BLM challenge-induced collagen. Even without the BLM challenge, overexpression of FLIL33 but not MIL33 moderately increased total lung collagen. Therefore, precursor IL-33 acts profibrotically without engaging ST2. Funding Sources NIH/NIAMS R01AR077562; VA I01BX006173 Topic Categories Cytokines and Chemokines and Their Receptors (CCR)