Regulation of bacteria-induced intercellular adhesion molecule-1 by CCAAT/enhancer binding proteins.
Direct interaction between bacteria and epithelial cells may initiate or amplify the airway response through induction of epithelial defense gene expression by nuclear factor-kappaB (NF-kappaB). However, multiple signaling pathways modify NF-kappaB 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-kappaB enhancer site. Constitutive C/EBPbeta was found to have an important role in epithelial cell ICAM-1 regulation, while the adjacent NF-kappaB sequence binds the RelA/p65 and NF-kappaB1/p50 members of the NF-kappaB 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/EBPbeta, 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/EBPbeta plays a central role in modulation of NF-kappaB-dependent defense gene expression in human airway epithelial cells after exposure to H. influenzae.
Manzel
Lori J
LJ
University of Iowa Carver College of Medicine, Department of Internal Medicine, 200 Hawkins Drive, C33-GH, Iowa City, IA 52242, USA.
Chin
Cecilia L
CL
Behlke
Mark A
MA
Look
Dwight C
DC
D001980:Bronchi / Q000276:immunology / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D006193:Haemophilus influenzae / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000276:immunology; D052002:NF-kappa B p50 Subunit; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014132:Trachea / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D052002:NF-kappa B p50 Subunit; C498143:RELA protein, human; D051996:Transcription Factor RelA; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases