UNDERSTANDING IMMUNE CELL SIGNALING: EFFECT OF RETINOIDS ON ADAM SHEDDING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Vitamin A (retinol) and its analogs, retinoids, are essential for many critical life processes, including establishment and maintenance of immunity. The literature is replete with studies on the influence of vitamin A on the growth and function of immune cells in model systems and organisms. Retinoids profoundly affect immune function by regulating the differentiation, proliferation, and trafficking of leukocytes. However, the mechanism by which retinoids govern these processes and maintain proper immunity is poorly understood. Retinoids, all-trans-retinoic acid (t-RA) and 9-cis-retinoic acid (9-cis-RA), act through nuclear retinoid receptors and function as ligand-dependent heterodimer transcription factors that alter the expression of ADAMs, a disintegrin and metalloproteases. ADAMs are human proteins involved in a spectrum of biological processes and are implicated in immune disease states, such as rheumatoid arthritis. ADAMs are a novel class of integrin ligand that is well characterized for executing the critical function of ectodomain shedding via proteolytic processing of molecules, including cytokines, growth factors, and, interestingly, retinoid receptors. The potential interplay between the adhesive and proteolytic functions of ADAMs remains poorly defined, but models developed by the Project Leader posit that protease specificity is bestowed by the integrin ligand properties of the disintegrin domain. Abnormal ADAM expression and/or disruption of ADAMintegrin complexes are believed to culminate in aberrant shedding events detrimental to normal cell function. To define the role of retinoids in immune-cell trafficking, this project will examine whether retinoids modulate immune functions of ADAMs with respect to adhesion and shedding. Our preliminary results have established that while some cell lineages are clearly retinoid-responsive, other cell types are nonresponsive with respect to cellular adhesion. Clearly, retinoid availability and retinoid receptor pairings mediated these events.