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Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Although it is widely accepted that glucocorticoids (GC) are a mainstay of the treatment of diseases characterized by airway inflammation, little is known about the effects of GC on local innate immunity. In this article, we report that respiratory epithelial cells manifested a local "acute phase response" after stimulation with TLR activation and TNF-
and that GC spared or enhanced the epithelial expression of molecules that are involved in host defense, including complement, collectins, and other antimicrobial proteins. As expected, GC inhibited the expression of molecules responsible for inflammation such as cytokines (IFN
and GM-CSF) and chemokines (RANTES and IL-8). Studies using Western blotting, EMSA, and functional analysis indicated that the selective effects of GC are mediated through activation of the transcription factor C/EBP. Knockdown of C/EBP by small interfering RNA blocked the enhancement by GC of host defense molecule expression but had no effect on inflammatory gene expression. These results suggest that GC spare or enhance local innate host defense responses in addition to exerting anti-inflammatory actions. It is possible that the known ability of GC to reduce the exacerbation of diseases in which infectious organisms serve as triggering factors (e.g., asthma, allergic bronchopulmonary aspergillosis, and chronic obstructive pulmonary disease) may result in part from enhanced innate immune responses in airway mucosa.
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 National Institutes of Health Grants HL068546 and HL078860 and a grant from Centocor.
2 N.Z. and Q.A.T.-T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Robert P. Schleimer, Allergy-Immunology Division, Northwestern University Feinberg School of Medicine, McGaw Pavilion M-318, 240 East Huron Street, Chicago, IL 60611. E-mail address: rpschleimer{at}northwestern.edu
4 Abbreviations used in this paper: APR, acute phase response; CRP, C-reactive protein; Ct, cycle threshold; FP, fluticasone propionate; GC, glucocorticoid; HBD, human -defensin; LAP, liver activating protein; LIP, liver inhibiting protein; MASP, mannose-binding lectin-associated serine protease; MBL, mannose-binding lectin; PBEC, primary bronchial epithelial cell; poly(I:C), polyinosinic acid:cytidylic acid; SAA, serum amyloid A; siRNA, small interfering RNA; SLPI, secretory leukocyte protease inhibitor; Sp, surfactant protein.
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