Human platelets contain and release TWEAK

Abstract

The multifunctional cytokine, TWEAK (TNF-like weak inducer of apoptosis), is a member of the TNFα superfamily. TWEAK is found in a broad range of cell types and has been linked to cell growth and survival, angiogenesis and other inflammatory processes. These functions and their importance in inflammatory diseases have made TWEAK an attractive pharmaceutical target, particularly for immunotherapy with monoclonal antibodies (mAbs). Immunotherapy targeting another TNFα family member, CD154, was associated with thrombosis in clinical trials. Subsequent studies identified platelets, which contain CD154, as a possible contributing factor to thrombosis in these trials. Since clinical trials with anti-TWEAK mAbs have already begun, we considered it important to determine whether platelets contain TWEAK. Using a variety of immunologic methods we found that, upon activation, human platelets expose TWEAK antigen and release it in soluble form (sTWEAK). By flow cytometry we determined that human platelets activated by TRAP (Thrombin Receptor Agonist Peptide) and other agonists expose TWEAK antigen (22% median positivity) and release TWEAK positive microparticles. The presence of TWEAK on platelets was confirmed by confocal microscopy. By ELISA, we found that sTWEAK is released by activated platelets. Finally, western blot analysis revealed TWEAK protein (34 kDa) in washed platelet lysates. The finding that human platelets contain TWEAK raises important questions about its possible functions in normal physiology, as well as in inflammatory diseases and their treatment.

GITR Ligand Provided by Thrombopoietic Cells Inhibits NK Cell Antitumor Activity

“…In this study, we describe that GITRL is upregulated during megakaryopoiesis, which results in GITRL expression by platelets. We found further that GITRL expression levels are upregulated upon platelet activation because of rapid translocation of preformed cellular protein to the platelet surface, which is similar to other TNF superfamily members expressed in platelets (25)(26)(27)30). Similar to other platelet-expressed TNF family members, platelet GITRL transduces forward signals into GITR + cells.…”

“…Previous data show expression of several TNF family members on platelets (25)(26)(27)(28)(29)(30)(31)(32)(33). In this study we set out to determine whether GITRL was expressed upon in vitro differentiation of megakaryocytes from CD34 + stem cells.…”

Platelets in tissue repair: control of apoptosis and interactions with regenerative cells

“…57 TNF-a is a major cytokine regulating apoptosis. 58 Although the presence of TNF-a in platelets is debatable, they store and secrete a variety of TNF-a-related ligands such as CD95 (Fas-L), 59 CD154 (CD40L), Apo2-L (TRAIL), 61 Apo3-L (TWEAK), 62 and LIGHT, 63 which have the potential of regulating apoptosis through paracrine signaling.…”

TWEAK Enhances E-selectin and ICAM-1 Expression, and May Contribute to the Development of Cutaneous Vasculitis

“…As a multifunctional cytokine, TWEAK mRNA is expressed in various tissues and cell lines [12]. In vitro, it has been reported that TWEAK can be released by inflammatory leukocytes, activated endothelial cells and activated platelets [13]–[15]. Therefore, it is plausible to propose that in CV, elevated serum concentration of TWEAK may result from excessive production by these cell types, which may interact with Fn14 on endothelial cells and play some roles in the pathogenesis of these diseases.…”