Attenuated innate mechanisms of interferon-gamma production in rats susceptible to postviral airway dysfunction.
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)-gamma treatment. We have shown that splenocytes from BN weanlings, compared with those from F344 weanlings, have a markedly reduced capacity for IFN-gamma production. We hypothesized that SeV-induced IFN-gamma production occurs via innate mechanisms that are attenuated in BN weanlings. Therefore, we investigated potential mechanisms of SeV-induced IFN-gamma production in BN and F344 weanlings. SeV-stimulated splenocytes secreted the IFN-gamma-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-gamma production. Anti-IL-12 antibody, IL-12 p40 homodimer, and IL-18 binding protein each inhibited SeV-induced IFN-gamma production by 82-94%, and the combination of IL-12 p40 homodimer and IL-18 binding protein abolished SeV-induced IFN-gamma production, demonstrating synergism between IL-12 and IL-18. Therefore, SeV-induced IFN-gamma production occurred via innate IL-12-, IL-18-, and natural killer cell-dependent mechanisms, which were attenuated in BN weanlings. Attenuation of innate IFN-gamma-producing responses to SeV in BN weanlings may be a critical factor in their susceptibility to postbronchiolitis chronic airway dysfunction.
Rosenthal
Louis A
LA
Morris Institute for Respiratory Research, University of Wisconsin Medical School, Madison, WI 53792, USA. lar@medicine.wisc.edu
Mikus
Lance D
LD
Tuffaha
Amjad
A
Mosser
Anne G
AG
Sorkness
Ronald L
RL
Lemanske
Robert F
RF
D000818:Animals; D001990:Bronchiolitis, Viral / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D010253:Respirovirus Infections / Q000378:metabolism*; D029082:Sendai virus / Q000378:metabolism*; D013154:Spleen / Q000166:cytology* / Q000378:metabolism / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma