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Essential Role of Nuclear Factor B in the Induction of Eosinophilia in Allergic Airway Inflammation

Liyan Yang^*, Lauren Cohn^*,, Dong-Hong Zhang^*, Robert Homer, Anuradha Ray^*, and Prabir Ray^*

From the ^* Department of Internal Medicine, Pulmonary and Critical Care Section, the Section of Immunobiology, and the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520

The molecular mechanisms that contribute to an eosinophil-rich airway inflammation in asthma are unclear. A predominantly T helper 2 (Th2)-type cell response has been documented in allergic asthma. Here we show that mice deficient in the p50 subunit of nuclear factor (NF)- B are incapable of mounting eosinophilic airway inflammation compared with wild-type mice. This deficiency was not due to a block in T cell priming or proliferation in the p50^–/– mice, nor was it due to a defect in the expression of the cell adhesion molecules VCAM-1 and ICAM-1 that are required for the extravasation of eosinophils into the airways. The major defects in the p50^–/– mice were the lack of production of the Th2 cytokine interleukin 5 and the chemokine eotaxin, which are crucial for proliferation and for differentiation and recruitment, respectively, of eosinophils into the asthmatic airway. Additionally, the p50^–/– mice were deficient in the production of the chemokines macrophage inflammatory protein (MIP)-1 and MIP-1β that have been implicated in T cell recruitment to sites of inflammation. These results demonstrate a crucial role for NF-B in vivo in the expression of important molecules that have been implicated in the pathogenesis of asthma.

Key Words: allergic inflammation • eosinophils • nuclear factor B • interleukin 5 • eotaxin

This paper is dedicated to the memory of our beloved mentor and friend Dr. Jyotirmoy Das of Indian Institute of Chemical Biology, India.

Abbreviations used: BAL, bronchoalveolar lavage; BALF, BAL fluid; EMSA, electrophoretic mobility shift assay; H&E, hematoxylin and eosin; ICAM, intercellular adhesion molecule; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; NF, nuclear factor; PLP, paraformaldehyde; RANTES, regulated on activation, normal T cell expressed and secreted; RT, reverse transcription; VCAM, vascular cell adhesion molecule.

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