The recent focus of the laboratory is to understand how airway epithelial cells modulate inflammation that leads to hyperreactive airways>and asthma. Airway epithelial cells are the first target for a variety of environmental stimuli. No longer thought of as inert barriers, airway epithelial cells (AEC) are now understood to have the capability to respond to stimuli such as local cytokines, infectious agents, pollutants andallergens. Their response to these stimuli alters the immune and inflammatory milieu of the airway that is critical in diseases such as asthma.

One response of AEC includes the expression of adhesion molecules critical for the recruitment of lymphocytes, eosinophils, neutrophils and dendritic cells. Intercellular adhesion molecule-1 (ICAM-1, CD54) is one such adhesion molecule and we have been studying mechanisms by which ICAM-1 expression may be altered in airway epithelial cells including the role of cytoskeletal proteins.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one critical cytokine involved in the immune and inflammatory response that can be released by AEC. This glycoprotein, a locally acting cytokine, has a multitude of effects important for initiating and perpetuating an immune response in the airway. In addition to its effects on eosinophils, it is critical for the recruitment, phenotypic differentiation, and activation of dendritic cells (DC), the most potent antigen presenting cells. In this capacity, the local release of GM-CSF by AEC provides a critical immunomodulatory signal in the airway. Since GM-CSF regulation is cell and stimulus specific we have been investigating mechanisms by which the production of GM-CSF is regulated in human bronchial epithelial cells. This information will further our understanding of the local regulation of expression of GM-CSF in a cell type critical for airway homeostasis.

Having demonstrated that the regulation of GM-CSF production differs between transformed human bronchial epithelial cells and primary culture human bronchial epithelial cells, we now perform all studies in primary culture bronchial epithelial cells (HBECs which we obtain during bronchoscopy of normal volunteer subjects.

To begin to understand the regulation of GM-CSF production in HBECs, we compared its regulation in these cells with that of T cells, and demonstrated that the regulation of GM-CSF differs between T cells and HBECs. To understand signal transduction pathways involved in GM-CSF protein and mRNA production in HBECs we have investigated the role of mitogen-activated-protein kinase (MAP kinase) pathways in these cells. Three distinct MAP kinase pathways have been identified in mammalian cells. These include the extracellular signal-regulated kinases (ERK1/ERK2), c-Jun N-terminal kinase (JNK kinase), and p38. Our data demonstrate an association and requirement for the ERK MAP kinase cascade for GM-CSF production in HBECs. Furthermore, our data suggest that ERK1/2 activation results in enhanced GM-CSF via an effect on GM-CSF mRNA stability. The role of additional MAP kinase pathways has yet to be defined.