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Regulation of Bacteria-Induced Intercellular Adhesion Molecule-1 by CCAAT/Enhancer Binding Proteins

¹ Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; and ² Integrated DNA Technologies, Coralville, Iowa

Correspondence and requests for reprints should be addressed to Dwight C. Look, M.D., University of Iowa Carver College of Medicine, Department of Internal Medicine, 200 Hawkins Drive, C33-GH, Iowa City, IA 52242. E-mail: dwight-look{at}uiowa.edu

Direct interaction between bacteria and epithelial cells may initiate or amplify the airway response through induction of epithelial defense gene expression by nuclear factor-B (NF-B). However, multiple signaling pathways modify NF-B effects to modulate gene expression. In this study, the effects of CCAAT/enhancer binding protein (C/EBP) family members on induction of the leukocyte adhesion glycoprotein intercellular adhesion molecule-1 (ICAM-1) was examined in primary cultures of human tracheobronchial epithelial cells incubated with nontypeable Haemophilus influenzae. Increased ICAM-1 gene transcription in response to H. influenzae required gene sequences located at –200 to –135 in the 5'-flanking region that contain a C/EBP-binding sequence immediately upstream of the NF-B enhancer site. Constitutive C/EBPβ was found to have an important role in epithelial cell ICAM-1 regulation, while the adjacent NF-B sequence binds the RelA/p65 and NF-B1/p50 members of the NF-B family to induce ICAM-1 expression in response to H. influenzae. The expression of C/EBP proteins is not regulated by p38 mitogen-activated protein kinase activation, but p38 affects gene transcription by increasing the binding of TATA-binding protein to TATA-box–containing gene sequences. Epithelial cell ICAM-1 expression in response to H. influenzae was decreased by expressing dominant-negative protein or RNA interference against C/EBPβ, confirming its role in ICAM-1 regulation. Although airway epithelial cells express multiple constitutive and inducible C/EBP family members that bind C/EBP sequences, the results indicate that C/EBPβ plays a central role in modulation of NF-B–dependent defense gene expression in human airway epithelial cells after exposure to H. influenzae.

Key Words: inflammation • transcription factors • NF-B • mitogen-activated protein kinase

CLINICAL RELEVANCE Haemophilus influenzae activates intercellular adhesion molecule-1 gene transcription in primary human airway epithelial cells. This work defines the importance of specific C/EBP family members and a mechanism for p38 mitogen-activated kinase modulation of defense gene expression.

 

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