TSG-14 transgenic mice have improved survival to endotoxemia and to CLP-induced sepsis

Tumor necrosis factor-stimulated gene 14 (TSG-14)/PTX3 was identified origi nally as a TNF-alpha and IL-1 beta -stimulated gene from normal, human fore skin fibroblasts and vascular endothelial cells, respectively. TSG-14 gene encodes a 42-kDa-secreted glycoprotein with a carboxy-terminal half that sh ares homology with the entire sequence of C-reactive protein (CRP) and seru m amyloid P component (SAP), acute-phase proteins of the pentraxin family. Some experimental evidence suggests that TSG-14 plays a role in inflammatio n, yet its function and mechanism of action remain unclear. Wie have genera ted transgenic mice that overexpress the murine TSG-14 gene under the contr ol of its own promoter. From eight transgenic founders, two lineages were d erived and better characterized: Tg2 and Tg4, carrying two and four copies of the transgene, respectively. TSG-14 transgenic mice were found to be mor e resistant to the endotoxic shock induced by LPS and to the polymicrobial sepsis caused by cecal ligation and puncture (CLP), Moreover, macrophages d erived from the transgenic mice produced higher amounts of nitric oxide in response to IFN-gamma, TNF-alpha, and LPS as compared with macrophages from wild-type animals, and the augmented response appears to be the consequenc e of a higher responsiveness of transgenic macrophages to IFN-gamma. The da ta shown here are the first in vivo evidence of the involvement of TSG-14 i n the inflammatory process and suggest a role for TSG-14 in the defense aga inst bacterial infections.