Shiga Toxin 1-Induced Inflammatory Response in LPS-Sensitized Astrocytes is Mediated by Endogenous TNF-alpha

LANDONI V.I; CAMPOS-NEBEL M; SCHIERLOH P; CALATAYUD C; FERNANDEZ G.C; RAMOS M.V; REARTE B; PALERMO M.S; ISTURIZ M.A

INFECTION AND IMMUNITY

Año: 2009

0019-9567

ABSTRACT Hemolytic uremic syndrome (HUS) is generally caused by Shiga Toxin (Stx)-producing E. coli. Endothelial dysfunction mediated by Stx is a central aspect in HUS development. However, inflammatory mediators such as bacterial lipopolysaccharide (LPS) and neutrophils (PMN) contribute to HUS pathophysiology by potentiating Stx effects. Acute renal failure is the main feature of HUS, but severe cases can develop neurological complications which are usually associated to death. Although the mechanisms of neurological damage remain uncertain, alterations of the blood brain barrier associated to brain endothelial injury is clear. Astrocytes (ASTs) are the most abundant inflammatory cells of the brain that modulate the normal function of brain endothelium and neurons. The aim of this study was to evaluate the effects of Stx type 1 (Stx1) alone or in combination with LPS in ASTs. Although Stx1 induced a weak inflammatory response, pretreatment with LPS sensitize ASTs to Stx1 mediated effects. Moreover, LPS increased the expression of Stx receptor and its internalization. An early inflammatory response, characterized by the release of TNF-á and nitric oxide, and PMN-chemoattractant activity, was induced by Stx1 in LPS-sensitized ASTs; whereas activation, evidenced by higher levels of glial fibrilary acid protein and cell death, were induced later. Furthermore, increased adhesion and PMN-mediated cytotoxicity were observed after Stx1 treatment in LPS-sensitized ASTs. These effects were dependent on NF-kB activation or ASTs-derived TNF-a. Our results suggest that TNF-a is a pivotal effector molecule that amplifies Stx1 effects on LPS-sensitized ASTs contributing to brain inflammation and leading to endothelial and neuronal injury.