Submitted on May 7, 2003
Revised on October 30, 2003
Attenuated Innate Mechanisms of IFN-
Production in Rats Susceptible to Postviral Airway Dysfunction
Louis A Rosenthal1*, Lance D Mikus1, Amjad Tuffaha2, Anne G Mosser1, Ronald L Sorkness3, and Robert F Lemanske, Jr.4
1 Medicine, University of Wisconsin Medical School, Madison, Wisconsin, USA,
2 Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin, USA,
3 Medicine, University of Wisconsin Medical School, Madison, Wisconsin, USA; Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin, USA; School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA,
4 Medicine, University of Wisconsin Medical School, Madison, Wisconsin, USA; Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin, USA
* To whom correspondence should be addressed. 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 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 (NK) 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 NK 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.
