Interleukin 12 P40 Production by Barrier Epithelial Cells during Airway Inflammation

doi:10.1084/jem.193.3.339

Published online 5 February 2001.

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© The Rockefeller University Press, 0022-1007/2001/2/339/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 3, February 5, 2001 339-352

Original Article

Interleukin 12 P40 Production by Barrier Epithelial Cells during Airway Inflammation

Michael J. Walter^a, Naohiro Kajiwara^a, Peter Karanja^a, Mario Castro^a, and Michael J. Holtzman^a^,b

^a Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
^b Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110
Washington University School of Medicine, Box 8052, 660 South Euclid Ave., St. Louis, MO 63110.314-362-8987314-362-8970

holtzmanm{at}msnotes.wustl.edu

Human airway epithelial cells appear specially programmed forexpression of immune response genes implicated in immunity andinflammation. To better determine how this epithelial systemoperates in vivo, we analyzed its behavior in mouse models thatallow for in vitro versus in vivo comparison and genetic modification.Initial comparisons indicated that tumor necrosis factor ${alpha}$ inductionof epithelial intercellular adhesion molecule 1 required sequentialinduction of interleukin (IL)-12 (p70) and interferon ${gamma}$ , andunexpectedly localized IL-12 production to airway epithelialcells. Epithelial IL-12 was also inducible during paramyxoviralbronchitis, but in this case, initial IL-12 p70 expression wasfollowed by 75-fold greater expression of IL-12 p40 (as monomerand homodimer). Induction of IL-12 p40 was even further increasedin IL-12 p35-deficient mice, and in this case, was associatedwith increased mortality and epithelial macrophage accumulation.The results placed epithelial cell overgeneration of IL-12 p40as a key intermediate for virus-inducible inflammation and acandidate for epithelial immune response genes that are abnormallyprogrammed in inflammatory disease. This possibility was furthersupported when we observed IL-12 p40 overexpression selectivelyin airway epithelial cells in subjects with asthma and concomitantincreases in airway levels of IL-12 p40 (as homodimer) and airwaymacrophages. Taken together, these results suggest a novel rolefor epithelial-derived IL-12 p40 in modifying the level of airwayinflammation during mucosal defense and disease.

Key Words: asthma • cell adhesion molecule • mucosal immunity • paramyxoviral bronchitis • macrophage

Abbreviations used in this paper: ANOVA, analysis of variance;BAL, bronchoalveolar lavage; EID₅₀, 50% egg infectious dose;ICAM, intercellular adhesion molecule; mTE, mouse tracheal epithelial;NF, nuclear factor; RANTES, regulated upon activation, normalT cell expressed and secreted; SdV, Sendai virus.

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