Distinct contributions of TNF receptor 1 and 2 to TNF-induced glomerular inflammation in mice

TNF is an important mediator of glomerulonephritis. The two TNF-receptors TNFR1 and TNFR2 contribute differently to glomerular inflammation in vivo, but specific mechanisms of TNFR-mediated inflammatory responses in glomeruli are unknown. We investigated their expression and function in murine kidneys, isolated glomeruli ex vivo, and glomerular cells in vitro. In normal kidney TNFR1 and TNFR2 were preferentially expressed in glomeruli. Expression of both TNFRs and TNF-induced upregulation of TNFR2 mRNA was confirmed in murine glomerular endothelial and mesangial cell lines. In vivo, TNF exposure rapidly induced glomerular accumulation of leukocytes. To examine TNFR-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wildtype and Tnfr-deficient mice following exposure to soluble TNF ex vivo. Most TNF-induced effects were exclusively mediated by TNFR1, including induced glomerular expression of adhesion molecules, chemokines, complement factors and pro-apoptotic molecules. However, TNFR2 contributed to TNFR1-dependent mRNA expression of inflammatory mediators in glomeruli when exposed to low TNF concentrations. Chemokine secretion was absent in TNF-stimulated Tnfr1-deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2. In vivo, TNF-induced glomerular leukocyte infiltration was abrogated in Tnfr1-deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils. These data demonstrate that activation of intrinsic glomerular cells by soluble TNF requires TNFR1, whereas TNFR2 is not essential, but augments TNFR1-dependent effects. Previously described TNFR2-dependent glomerular inflammation may therefore require TNFR2 activation by membrane-bound, but not soluble TNF

Anti-inflammatory strategies in hypertension: focus on COX-1 and COX-2

An increasing body of evidence suggests that elevated levels of blood pressure may induce a proinflammatory response. Indeed, both C-reactive protein and blood pressure are independent determinants of cardiovascular risk, and, in combination, each parameter has additional predictive value. Hence, strategies targeted to lower blood pressure and reduce vascular inflammation may potentially provide clinical benefit. In this review, we discuss the role of chronic low-grade inflammation in the context of cardiovascular disease with a focus on roles of cyclooxygenase-1 and -2 in potential anti-inflammatory treatment strategies

Mechanisms of damage and repair in multiple sclerosis--a review.

Pathological features of MS include perivascular inflammation and demyelination with oligodendrocyte loss; in addition, attempts at remyelination are often unsuccessful and may culminate in astrocytic scarring. One approach to investigating the biological principles underlying these processes is to use in vitro systems to analyse single-cell behaviour as well as cell-cell interactions. This paper reviews such data concerned with cell injury and repair which illuminate both demyelination and remyelination. In tissue culture oligodendrocytes are susceptible to injury via cell-mediated and humoral mechanisms. Substances including complement and tumour necrosis factor are capable of killing rat oligodendrocytes in vitro; surface complement activation also initiates a number of intracellular processes within oligodendrocytes as well as providing ligands for phagocytic interactions. The reasons for oligodendrocyte complement activation are discussed, but it appears that species differences exist when extrapolating these data to humans. Myelination and remyelination can also be studied both in vitro and in vivo using defined cell populations. Results from these studies may eventually help to explain some pathological features of MS, including astrocytosis and factors governing the limits of remyelination.</p