RESUMEN
OBJECTIVES: To review the physiological and physiopathological roles of pentraxin 3 (PTX3), focusing on autoimmunity and vascular pathology. METHODS: A systematic literature review using the keywords "pentraxin 3," "innate immunity," "apoptosis," "autoimmunity," and "endothelial dysfunction" from 1990 to 2007 was performed. All relevant articles and pertinent secondary references in English were reviewed. RESULTS: PTX3 has a large number of multiple functions in different contexts. PTX3 plays an important role in innate immunity, inflammation, vascular integrity, fertility, pregnancy, and also in the central nervous system. In innate immunity, its normal function is to increase the immune response to selected pathogens while also exerting control over potential autoimmune reactions. It maintains a tightly homeostatic equilibrium in the local immune microenvironment by avoiding an exaggerated immune response and controlling peripheral tolerance to self-antigens. In contrast, in some autoimmune diseases, PTX3 appears to be involved in the development of autoimmune phenomena. A possible explanation for these apparent paradoxical functions may be related to the highly polymorphic PTX3 gene. CONCLUSION: PTX3 is physiologically a protective molecule. However, in several autoimmune diseases PTX3 appears to facilitate the development of autoimmunity. The PTX3 gene could influence the development of autoimmune reactions and vascular involvement in human pathology.
Asunto(s)
Autoinmunidad/fisiología , Proteína C-Reactiva/fisiología , Componente Amiloide P Sérico/fisiología , Proteína C-Reactiva/química , Endotelio Vascular/fisiopatología , Humanos , Inmunidad Innata/fisiología , Componente Amiloide P Sérico/química , Enfermedades Vasculares/fisiopatologíaRESUMEN
TSG-14/PTX3 is a gene inducible by tumor necrosis factor (TNF)-alpha, interleukin-1 beta, and lipopolysaccharide in fibroblasts, macrophages, and endothelial cells. It encodes a 42-kd secreted glycoprotein that belongs to the pentraxin family of acute-phase proteins. Recently, we demonstrated that TSG-14 transgenic mice (TSG-14tg) overexpressing the murine TSG-14 gene under control of its own promoter are more resistant to lipopolysaccharide-induced shock and to polymicrobial sepsis caused by cecal ligation and puncture. Here we show that after ischemia and reperfusion (I/R) injury, TSG-14tg mice have an impaired survival rate, which appeared secondary to a markedly increased inflammatory response, as assessed by the local (duodenum and ileum) and remote (lung) enhancement in vascular permeability, hemorrhage, and neutrophil accumulation. Moreover, tissue concentrations of TNF-alpha, interleukin-1 beta, KC, and MCP-1 were higher in TSG-14tg as compared to wild-type mice after I/R injury. Of note, elevated TNF-alpha concentrations in serum were only observed in TSG-14tg mice and blockage of TNF-alpha action prevented lethality of TSG-14tg mice. These results demonstrate that transgenic expression of TSG-14 induces an enhanced local and systemic injury and TNF-alpha-dependent lethality after I/R. Taken together, our data point to a critical role of TSG-14 in controlling acute inflammatory response in part via the modulation of TNF-alpha expression.
Asunto(s)
Proteína C-Reactiva/fisiología , Inflamación/patología , Daño por Reperfusión/fisiopatología , Componente Amiloide P Sérico/fisiología , Animales , Antígenos CD/genética , Antígenos CD/fisiología , Proteína C-Reactiva/genética , Permeabilidad Capilar/fisiología , Quimiocinas/metabolismo , Citocinas/metabolismo , Duodeno/irrigación sanguínea , Duodeno/metabolismo , Duodeno/patología , Regulación de la Expresión Génica , Genotipo , Inflamación/etiología , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Transgénicos , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/fisiología , Receptores Tipo I de Factores de Necrosis Tumoral , Daño por Reperfusión/complicaciones , Daño por Reperfusión/mortalidad , Componente Amiloide P Sérico/genética , Tasa de Supervivencia , Factores de TiempoRESUMEN
Tumor necrosis factor-stimulated gene 14 (TSG-14)/PTX3 was identified originally as a TNF-alpha and IL-1beta-stimulated gene from normal, human foreskin fibroblasts and vascular endothelial cells, respectively. TSG-14 gene encodes a 42-kDa-secreted glycoprotein with a carboxy-terminal half that shares homology with the entire sequence of C-reactive protein (CRP) and serum amyloid P component (SAP), acute-phase proteins of the pentraxin family. Some experimental evidence suggests that TSG-14 plays a role in inflammation, yet its function and mechanism of action remain unclear. We have generated transgenic mice that overexpress the murine TSG-14 gene under the control of its own promoter. From eight transgenic founders, two lineages were derived and better characterized: Tg2 and Tg4, carrying two and four copies of the transgene, respectively. TSG-14 transgenic mice were found to be more resistant to the endotoxic shock induced by LPS and to the polymicrobial sepsis caused by cecal ligation and puncture (CLP). Moreover, macrophages derived 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 consequence of a higher responsiveness of transgenic macrophages to IFN-gamma. The data shown here are the first in vivo evidence of the involvement of TSG-14 in the inflammatory process and suggest a role for TSG-14 in the defense against bacterial infections.