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Type I Interleukin-1 Receptor Is Required for Pulmonary Responses to Subacute Ozone Exposure in Mice

Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Richard A. Johnston, Ph.D., Room 8.104A, Medical Research Building, Division of Allergy, Pulmonary, Immunology, Critical Care, and Sleep, Department of Internal Medicine, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1083. E-mail: rajohnst{at}utmb.edu

Interleukin (IL)-1, a proinflammatory cytokine, is expressed in the lung after ozone (O₃) exposure. IL-1 mediates its effects through the type I IL-1 receptor (IL-1RI), the only signaling receptor for both IL-1 and IL-1. The purpose of this study was to determine the role of IL-1RI in pulmonary responses to O_3. To that end, wild-type, C57BL/6 (IL-1RI^+/+) mice and IL-1RI–deficient (IL-1RI^–/–) mice were exposed to O₃ either subacutely (0.3 ppm for 72 h) or acutely (2 ppm for 3 h). Subacute O₃ exposure increased bronchoalveolar lavage fluid (BALF) protein, interferon-–inducible protein (IP)-10, soluble tumor necrosis factor receptor 1 (sTNFR1), and neutrophils in IL-1RI^+/+ and IL-1RI^–/– mice. With the exception of IP-10, all outcome indicators were reduced in IL-1RI^–/– mice. Furthermore, subacute O₃ exposure increased IL-6 mRNA expression in IL-1RI^+/+, but not IL-1RI^–/– mice. Acute (2 ppm) O₃ exposure increased BALF protein, IL-6, eotaxin, KC, macrophage inflammatory protein (MIP)-2, IP-10, monocyte chemotactic protein-1, sTNFR1, neutrophils, and epithelial cells in IL-1RI^+/+ and IL-1RI^–/– mice. For IL-6, eotaxin, MIP-2, and sTNFR1, there were small but significant reductions of these outcome indicators in IL-1RI^–/– versus IL-1RI^+/+ mice at 6 hours after exposure, but not at other time points, whereas other outcome indicators were unaffected by IL-1RI deficiency. These results suggest that IL-1RI is required for O₃-induced pulmonary inflammation during subacute O₃ exposure, but plays a more minor role during acute O₃ exposure. In addition, these results suggest that the induction of IL-6 via IL-1RI may be important in mediating the effects of O₃ during subacute exposure.

Key Words: bronchoalveolar lavage • interleukin-6 • macrophage • neutrophil • soluble tumor necrosis factor receptor

CLINICAL RELEVANCE IL-1RI, the only signaling receptor for IL-1 and IL-1, is important for pulmonary inflammatory responses to subacute O3 exposure, likely through induction of IL-6. However, IL-1RI is less important for lung inflammatory responses to acute O3 exposure.