Airway epithelial cells express receptors for proinflammatory cytokines, such as tumor necrosis factor-a (TNF-a) and interleuken-1 (IL-1), and therefore represent target cells for autocrine or paracrine acting cytokines. Airway epithelial cells may modulate cytokine-mediated events via the shedding of cell surface receptors or by the production of receptor antagonists. Airway epithelial cells express the 55 kDa type I TNF receptor, which can be proteolytically cleaved to function as a soluble TNF binding protein. We have reported that protein kinase C activation by phorbol ester or IL-1a can induce shedding of the 55 kDa type I TNF receptor from human airway epithelial cells (HAEC), a condition associated with a decrease in total cellular 55 kDa type I TNF receptor numbers. Conversely, corticosteroids inhibit TNF receptor shedding and increase total cellular 55 kDa type I TNF receptor numbers. Studies are now under way to investigate the mechanisms underlying TNF receptor shedding and to identify the enzyme responsible for proteolytic cleavage. HAEC also express the type I intracellular isoform of the interleukin-1 receptor antagonist (icIL-1Ra type I). We have reported that corticosteroids induce icIL-1Ra type I mRNA and protein as a mechanism by which IL-1-mediated airway inflammatory events might be attenuated. Another manuscript has been completed describing the differential regulation of icIL-1Ra release from HAEC by corticosteroids and cytokines. IL-4, IL-13 and interferon-a induce icIL-1Ra type I release to the extracellular compartment, while corticosteroids inhibit release, thereby allowing for the accumulation of icIL-1Ra type I within the intracellular compartment. Additional studies are in progress to investigate the mechanism underlying icIL-1Ra type I release and to understand its role as a regulator of intracellular IL-1 bioactivity. An increased understanding of the mechanisms by which epithelial cells modulate responses to inflammatory cytokines may allow for the development of new therapeutic approaches to reduce airway inflammation.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Intramural Research (Z01)
Project #
1Z01CL000177-03
Application #
6103585
Study Section
Special Emphasis Panel (CCMD)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
United States
Zip Code