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Pathogenesis of Steroid-Resistant Airway Hyperresponsiveness: Interaction between IFN- and TLR4/MyD88 Pathways ¹

Ming Yang^2,*, Rakesh K. Kumar and Paul S. Foster^2,*

^* Centre for Asthma and Respiratory Disease, School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan, Australia; Department of Pathology, School of Medical Sciences, University of New South Wales, Sydney, Australia

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- and endotoxins are also related to severe asthma and because these activate host defense pathways, we investigated a possible common etiologic link to steroid-resistant 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 OVA_323–339 peptide-specific IFN--producing Th1 cells into mice. These animals were subsequently challenge via the airways with OVA_323–339 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-, 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 OVA_323–339 peptide-activated Th2 cells, eosinophilic inflammation and AHR were induced, and both were suppressed by steroid treatment. We conclude that cooperative signaling between IFN- and TLR4/MyD88 constitutes a previously unrecognized pathway that regulates macrophage-dependent steroid-resistant AHR.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by project grants from the National Health & Medical Research Council of Australia (to P.S.F., R.K.K., and M.Y.) and the Cooperative Research Centre for Asthma and Airways (to P.S.F.).

² Address correspondence and reprint requests to Dr. Paul S. Foster and Dr. Ming Yang, School of Biomedical Sciences, University of Newcastle, 5th Floor, David Maddison Clinical Sciences Building, CNR Watt and King Streets, Newcastle NSW 2300, Australia. E-mail addresses: Paul.Foster{at}newcastle.edu.au and Ming.Yang{at}newcastle.edu.au

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; i.n., intranasal(ly); i.t., intratracheally; 2-CA, 2-choloradenosine; DHR, dihydrorhodamine 123; KO, knockout; WT, wild type; BALF, bronchoalveolar lavage fluid.