Role of Interleukin-12 and Stat-4 in the Regulation of Airway Inflammation and Hyperreactivity in Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is a respiratory pathogen that can cause significant morbidity in infants and young children. Interestingly, the majority of children who acquire a RSV infection do not exhibit severe symptoms. Development of a Th1 response has been associated with resolution of symptoms in viral infections and may explain mild RSV illness. The current study investigated the cytokine response observed in mild disease in C57BL/6 mice that had low airway resistance and mucus production with little pulmonary inflammation. RSV infection in these mice was accompanied by a fourfold increase in interleukin-12(IL-12). Treatment of RSV-infected mice with anti-IL-12 resulted in an increase in airway hyperreactivity, mucus production, and airway inflammation (eosinophilia). Since IL-12 activation is dependent on Stat-4-mediated intracellular signal transduction, similar experiments were performed in Stat-4 deficient mice and demonstrated similar results to those obtained from anti-IL-12 treated mice. Again, there was an increase in airway hyperreactivity and mucus production, and goblet cell hypertrophy. These studies support the importance of IL-12 in the immune response to RSV infection resulting in resolution of disease and protection from inappropriate inflammatory responses.

Deletion of TLR3 Alters the Pulmonary Immune Environment and Mucus Production during Respiratory Syncytial Virus Infection

“…Previous studies have demonstrated that TLR3 has an integral role for responding to dsRNA (28 -31), a required intermediate for RSV that is a negative strand virus. It is important to note that previous studies have shown that this strain of mouse readily clears RSV and has little associated pathogenic response (27,32,33). The present studies found no significant difference in the TLR3 Ϫ/Ϫ animals' ability to clear RSV, compared with wild-type control mice, examining RSV-specific pulmonary titers during infection (data not shown).…”

“…Human RSV A strain, originally isolated at University of Michigan Hospitals, was propagated in Hep2 cells as previously described (25)(26)(27). To determine viral titers, a plaque assay was performed in Vero cells that were grown until they were semiconfluent.…”

“…Mice were infected intratracheally with ϳ1 ϫ 10 5 PFU of human RSV A strain virus isolated from University of Michigan Hospitals and used as previously described (25)(26)(27). Animals were then maintained under biohazard containment in University of Michigan animal facilities.…”

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

“…Our laboratory has previously shown that the up-regulation of IL-13 in RSV-infected BALB/c exacerbates mucus production, airway hyperreactivity, and airway inflammation (9 -11), whereas others have indicated that the age of infection can influence the production of IL-13 (12). Conversely, IL-12 in RSV-infected C57BL/6 mice creates a more protective immune environment by limiting mucus overexpression, airway hyperreactivity, and eosinophilia (13). IL-12 is primarily produced by activated APCs in the lung and promotes the development of Th1 immune cells and cell-mediated immunity (14).…”

“…We previously have demonstrated that C57BL/6 mice infected with RSV respond with a more protective immune response and exhibit only mild pathophysiology (13). To test the hypothesis that TLR signaling is critical in generating an appropriate nonpathogenic immune response, we first compared lung inflammation in MyD88 Ϫ/Ϫ and C57BL/6 mice infected with RSV.…”