Immunomodulatory effects of factor Xa.
Published: 2005
Language: eng
Number of pages: 163
Description: The serine protease factor Xa (FXa) plays a central role in the coagulation cascade, catalyzing the conversion of prothrombin to thrombin at sites of vascular injury. In addition, FXa has been shown to mediate a variety of other biologic effects that are not related to hemostasis. Conflicting reports have suggested that such FXa effects may include T cell proliferation and costimulation, but the nature of these putative responses remains obscure. To clarify this issue, I have characterized in detail the response of purified human T cells to FXa. I demonstrate that FXa stimulation results in the rapid activation of MAPK, and induces T cell proliferation (involving both CD4+ and CD8+ cells) and secretion of the Th1/Th2 cytokines IL-2, IFN-gamma and IL-4, with cytokine levels increasing by as much as several fold in ten different donors tested. Such FXa effects are observed even in the absence of anti-CD28, consistent with the notion that FXa can mediate a costimulatory signal to human T cells. However, the effect of FXa may not be able to completely replace CD28, and is most likely additive in enhancing survival and proliferative signals. FXa-induced T cell proliferative and cytokine effects are direct and thrombin-independent, and are not duplicated by FIXa. Moreover, as the intact zymogen FX, an active-site-inhibited form of FXa, and a peptide corresponding to the inter-EGF domain of FXa, do not duplicate these effects, it is likely that the serine protease activity of FXa is required for this activity, and that the putative FXa receptor---effector-cell protease receptor-1 (EPR-1)---is not involved in this response. Rather, I demonstrate by RT-PCR, Western blotting, and FACS analysis that purified human T cells express all four protease activated receptors (PARs), and that their expression varies in an activation-dependent manner. Furthermore, I illustrate by receptor blockade and desensitization that FXa likely mediates its effects on T cells via the receptors PAR1 and PAR2. Finally, this work demonstrates conclusively that FXa is an important link between blood coagulation and the immune system.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5308.

Thesis (Ph.D.)--University of Toronto, 2005.

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