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Function and Regulation of SPLUNC1 Protein in Mycoplasma Infection and Allergic Inflammation¹

Hong Wei Chu^2,*, Jyoti Thaikoottathil^*, John G. Rino^*, Gongyi Zhang, Qun Wu^*, Taylor Moss^*, Yosef Refaeli, Russell Bowler^*, Sally E. Wenzel, Zhongzhou Chen, Jeffrey Zdunek^*, Rachel Breed^*, Ryan Young, Erin Allaire^* and Richard J. Martin^*

^* Department of Medicine, Department of Immunology, and Department of Pediatrics, National Jewish Medical and Research Center and the University of Colorado Health Sciences Center, Denver, CO 80206 and Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15260

Respiratory infections, including Mycoplasma pneumoniae (Mp), contribute to asthma pathobiology. To date, the mechanisms underlying the increased susceptibility of asthmatics to airway Mp infection remain unclear. Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is a recently described large airway epithelial cell-derived molecule that was predicted to exert host defense activities. However, SPLUNC1 function and regulation in an infectious or allergic milieu are still unknown. We determined host defense and anti-inflammatory functions of SPLUNC1 protein in Mp infection and the regulation of SPLUNC1 by Mp and allergic inflammation (e.g., IL-13). SPLUNC1 function was examined in Mp or human airway epithelial cell cultures by using SPLUNC1 recombinant protein, overexpression and RNA interference. Human and mouse bronchial epithelial SPLUNC1 was examined using immunostaining, Western blotting, ELISA, laser capture microdissection, and real-time PCR. Mouse models of Mp infection and allergic inflammation and air-liquid interface cultures of normal human primary bronchial epithelial cells were used to study SPLUNC1 regulation by Mp and IL-13. We found that: 1) SPLUNC1 protein decreased Mp levels and inhibited epithelial IL-8 production induced by Mp-derived lipoproteins; 2) normal human and mouse large airway epithelial cells expressed high levels of SPLUNC1; and 3) although Mp infection increased SPLUNC1, IL-13 significantly decreased SPLUNC1 expression and Mp clearance. Our results suggest that SPLUNC1 serves as a novel host defense protein against Mp and that an allergic setting markedly reduces SPLUNC1 expression, which may in part contribute to the persistent nature of bacterial infections in allergic airways.

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 is supported by National Institutes of Health Grant PO1 HL073907 and the Flight Attendant Medical Research Institute.

² Address correspondence and reprint requests to Dr. Hong Wei Chu, National Jewish Medical and Research Center, 1400 Jackson Street, Room A639, Denver, CO 80206. E-mail address: chuhw{at}njc.org

³ Abbreviations used in this paper: Mp, Mycoplasma pneumoniae; ALI, air-liquid interface; BAL, bronchoalveolar lavage; BPI, bactericidal/permeability increasing (protein); ffu, focus-forming unit; hSPLUNC1, human SPLUNC1; LCM, laser capture microdissection; mSPLUNC1, mouse SPLUNC1; Pam3CSK4, (S)-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys₄-OH, 3HCl; PLUNC, palate, lung, and nasal epithelium clone; PPLO, pleuropneumonia-like organism; shRNA, short hairpin RNA; SPLUNC1, short PLUNC1; VSV-G, vesicular stomatitis virus envelope glycoprotein.

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