MECHANISM OF MATRIX MODULATION OF IL 1 SIGNALING

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IL-1 is a central mediator of inflammation. IL-1 binding to its receptor activates two separate pathways map-2 kinase and NF-kappa-B, but the initial events of signal transduction are not known. Studies on the effect on the extracellular matrix metabolism show that IL-1 regulation of proteoglycans and collagen mRNA levels are dependent on fibronectin attachment. IL-1 receptors are located at focal adhesions and IL-1 binding causes changes in cell-matrix interaction and alterations in the cytoskeleton. We have found that IL-1 receptor binding is affected by fibronectin attachment. Further, our ongoing studies show that IL-1 activation of both map-2 kinase and NF-kappaB are affected by fibronectin attachment. Such changes could be caused by activation of additional signaling pathways interfering with the IL-1 induced activation. In addition, they could be a result of change in matrix sensitive messengers in the IL-1 activated pathway either upstream, or at the level of map-2 kinase and NF-Kappa-B respectively. Experiments described in the present proposal will determine the mechanisms involved in the matrix/cell- attachment induced effect on IL-1 signal transduction. We will determine whether the matrix induced kinase, the focal adhesion activated kinase p125FAK, influences the IL-1 induced pathways. In addition, we will study second messengers, upstream in the IL-1 induced pathway or activated by other cytokines and growth factors, in particular those with specific effects on structural relations, and determine the effect of cell-matrix interaction on their regulation. Further, we will determine if the changes in signaling can be partly explained by qualitative alterations of map-2 kinase and NF-kappaB. Finally, we will use the collagen promotor to determine that-these changes in signaling actually are responsible for the induced alterations in the biological response by studying the matrix induced effect in mutants with lacking or altered NF-kappaB and AP-1 binding sites. These studies will increase our understanding of interdependence of signaling between cytokines and the extracellular matrix by determining the pathways and the mechanism(s) involved and thus, help further clarify the regulation of IL-1 during inflammation.