Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/806856
- Pathogenesis of steroid-resistant airway hyperresponsiveness: interaction between IFN-γ and TLR4/MyD88 pathways
Kumar, Rakesh K.;
Foster, Paul S.
- The University of Newcastle. Faculty of Health, School of Biomedical Sciences and Pharmacy
- Chronic inflammation and airway hyperresponsiveness (AHR) in asthmatics are usually managed effectively by treatment with glucocorticoids. However, a subset of patients remains refractory to therapy. The underlying mechanisms are largely unknown, although recruitment of neutrophils (rather than eosinophils) is strongly correlated, suggesting a role for nonallergic host defense responses. Increased levels of IFN-γ and endotoxins are also related to severe asthma and because these activate host defense pathways, we investigated a possible common etiologic link to steroid- esistant disease. To be able to unravel the complexity of asthmatic inflammation, we used two model systems which permitted dissection of the relevant molecular pathways. In the first of these, we transferred transgenic OVA₃₂₃₋₃₃₉ peptide-specific IFN-γ-producing Th1 cells into mice. These animals were subsequently challenge via the airways with OVA₃₂₃₋₃₃₉ peptide and/or LPS. Challenge with both components, but not with either one individually, induced AHR. Importantly, AHR was resistant to treatment with dexamethasone. Development of AHR was dependent on IFN-γ, inhibited by depletion of pulmonary macrophages (but not neutrophils) and abrogated in TLR4- or MyD88-deficient mice. In contrast, in the second model in which we transferred OVA₃₂₃₋₃₃₉ peptide-activated Th2 cells, eosinophilic inflammation and AHR were induced, and both were suppressed by steroid treatment. We conclude that cooperative signaling between IFN-γ and TLR4/MyD88 constitutes a previously unrecognized pathway that regulates macrophage-dependent steroid-resistant AHR.
- Journal of Immunology Vol. 182, Issue 8, p. 5107-5115
- Publisher Link
- American Association of Immunologists
- Resource Type
- journal article