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Attenuated Innate Mechanisms of Interferon- Production in Rats Susceptible to Postviral Airway Dysfunction

Morris Institute for Respiratory Research, and Departments of Medicine and Pediatrics, University of Wisconsin Medical School; and School of Pharmacy, University of Wisconsin–Madison, Madison, Wisconsin

Address correspondence to: Louis A. Rosenthal, Ph.D., University of Wisconsin Medical School, K4-948 CSC-9988, 600 Highland Avenue, Madison, WI 53792. E-mail: lar{at}medicine.wisc.edu

After Sendai virus (SeV)-induced bronchiolitis as weanlings, BN, but not F344, rats develop a postbronchiolitis asthma-like phenotype, which can be prevented by supplemental interferon (IFN)- treatment. We have shown that splenocytes from BN weanlings, compared with those from F344 weanlings, have a markedly reduced capacity for IFN- production. We hypothesized that SeV-induced IFN- production occurs via innate mechanisms that are attenuated in BN weanlings. Therefore, we investigated potential mechanisms of SeV-induced IFN- production in BN and F344 weanlings. SeV-stimulated splenocytes secreted the IFN-–inducing cytokines, interleukin (IL)-12 and IL-18. BN splenocytes produced significantly less IL-12 (P = 0.001) and IL-18 (P < 0.001) than did F344 splenocytes. Depletion studies demonstrated that natural killer cells were the primary source of SeV-induced IFN- production. Anti–IL-12 antibody, IL-12 p40 homodimer, and IL-18 binding protein each inhibited SeV-induced IFN- production by 82–94%, and the combination of IL-12 p40 homodimer and IL-18 binding protein abolished SeV-induced IFN- production, demonstrating synergism between IL-12 and IL-18. Therefore, SeV-induced IFN- production occurred via innate IL-12–, IL-18–, and natural killer cell–dependent mechanisms, which were attenuated in BN weanlings. Attenuation of innate IFN-–producing responses to SeV in BN weanlings may be a critical factor in their susceptibility to postbronchiolitis chronic airway dysfunction.

Abbreviations: analysis of variance, ANOVA • enzyme-linked immunosorbent assay, ELISA • interferon, IFN • interleukin, IL • chimeric protein linking IL-18 binding protein a and Fc region of IgG₁, IL-18BPa/Fc • natural killer, NK • peripheral blood mononuclear cells, PBMC • plaque-forming units, pfu • respiratory syncytial virus, RSV • Sendai virus, SeV