Mark Moore

Tumor necrosis factor receptors (Tnfr) in mouse fibroblasts deficient in Tnfr1 or Tnfr2 are signaling competent and activate the mitogen-activated protein kinase pathway with differential kinetics.

To dissect tumor necrosis factor receptor (Tnfr)-1 (CD120a) and Tnfr2 (CD120b)-dependent signal transduction pathways, primary fibroblasts isolated from inguinal adipose tissue of wild type (wt), tnfr1o, tnfr2o, and tnfr1o/tnfr2o mice were studied. The mitogen-activated protein kinases Erk1 and Erk2 were found to be tyrosine-phosphorylated and activated by Tnf treatment in all wt, tnfr1o, and tnfr2o fibroblasts; the activation was down-regulated 60 min after the start of steady state Tnf treatment. Distinct kinetics of Erk1 and Erk2 activation were detected; the Tnfr1-mediated activation of Erk1 and Erk2 started more slowly and persisted for more prolonged times as compared with Tnfr2 activation. Raf-1, Raf-B, Mek-1, Mek kinase, and p90rsk kinases were also shown to be activated independently in a distinct time-dependent pattern through the two Tnf receptors. In addition, both Tnfr1 and Tnfr2 mediated independently the activation of the transcription factor Ap-1 albeit with parallel activation kinetics. In contrast, Tnfr1 exclusively mediated activation of NF-κB and fibroblast proliferation; however, Tnfr2 enhanced proliferation triggered through Tnfr1. These findings indicate distinct but also overlapping roles of Tnfr1 and Tnfr2 in primary mouse fibroblasts and suggest different regulation mechanisms of signal transduction pathways under the control of both Tnf receptors.

Respective role of TNF receptors in the development of experimental cerebral malaria

The respective role of the two receptors of TNF in experimental cerebral malaria (CM) was investigated. During CM, a significant upregulation of TNF-receptor 2 (TNFR2), but not of TNFR1, was found in brain microvessels of susceptible, but not resistant mice. Mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from CM, while TNFR1-deficient (Tfnr1null) mice were as susceptible as wild-type mice. The protection of Tnfr2null mice could be explained by their absence of ICAM-1 upregulation and leukocyte sequestration, known to occur in brain microvessels of CM-susceptible animals.

Neutrophilia and B-Cell Plasmacytosis in Mice Lacking the Murine IL-8 Receptor Homolog

Interleukin-8 (IL-8) is a member of a family of proinflammatory cytokines containing four conserved cysteine residues that are related by a C-X-C motif, and is a major factor in acute inflammation, being responsible for the activation and chemotaxis of neutrophils to the site of acute injury (1–5). Neutrophils provide the first line of defense in fighting infection by destroying bacteria with phagocytosis and the release of super oxides and peroxides. The response is rapid and is neither acquired nor antigen specific (6,7). With sepsis or trauma, this usually beneficial response can result in death since an excess of activated neutrophils can produce extensive organ and tissue damage. IL-8 is produced by a large variety of cell types in vitro and has been implicated in neutrophil migration and, to a lesser extent, T-cell migration, to sites of IL-8 injection (8–10). Despite rapid advances in the chemokine field, there has been some frustration in developing small animal models of IL-8 mediated inflammation as neither mouse nor rat IL-8 has been identified (11). Reports that anti-human IL-8 antibodies inhibit lung inflammation in rats (12) suggest the presence of a similar molecule in rodents. Because of the tremendous importance of this molecule in humans, dogs, and rabbits, it is likely that if there is not a murine equivalent of IL-8 then other factor(s) must mediate similar physiological events.