We explored the role of the transcription factor c-Fos in lipopolysaccharide (LPS)-induced cytokine response using mice lacking c-Fos (Fos-/- mice). Compared with wild-type controls, Fos-/- macrophages and mice showed significantly enhanced production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12 p40, but reduced production of the anti-inflammatory cytokine IL-10. Bandshift analysis revealed that LPS-induced NF-kappaB binding activity to a functional site in the TNF-alpha promoter was significantly higher in Fos-/- than in wild-type macrophages. Using telemetry, we monitored body temperature and heart rate after LPS injection and found that Fos-/- mice undergo more severe hypothermia and bradycardia than wild-type mice. Such shock responses in Fos-/- mice were significantly reversed by neutralizing TNF-alpha. These data reveal a novel in vivo role for c-Fos as an anti-inflammatory transcription factor acting through suppression of NF-kappaB activity.

The Fos family proteins, c-Fos and Fra-1, are components of the dimeric transcription factor AP-1, which is typically composed of Fos and Jun family proteins. We have previously shown that mice lacking c-Fos (Fos−/− mice) respond more strongly to LPS injection than do wild-type (wt) controls. We then examined the sensitivity of Fos−/− mice to acute inflammatory stress in a dextran sulfate sodium (DSS)-induced colitis model. We found that Fos−/− mice exhibited more severe weight loss, bleeding, diarrhea, and colon shortening than did wt mice, in association with higher TNF-α production and NF-κB activity in colon segments of DSS-treated Fos−/− mice. Furthermore, NF-κB inhibition suppressed severe DSS-induced colitis in Fos−/− mice. In contrast, Fra-1 transgenic (Tg) mice responded poorly to LPS injection, and Fra-1–overexpressing macrophages and fibroblasts showed reduced production of proinflammatory cytokines, NO, and NF-κB activity. Remarkably, in the DSS-induced colitis model, Fra-1 Tg mice showed less severe clinical scores of colitis than did wt mice. Consistently, proinflammatory cytokine production and NF-κB activity in colon segments of DSS-treated Fra-1 Tg mice were lower than in wt controls. These findings reveal that the absence of c-Fos and overexpression of Fra-1 respectively enhance and suppress the activation of NF-κB in DSS-induced inflammatory stress. In this paper, we propose that AP-1 transcription factors containing c-Fos or Fra-1 are negative regulators of NF-κB–mediated stress responses.

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Abstract:Although the effect of taurine on the heart and liver is well studied, there has been no direct observation concerning the effect of taurine on spatial learning and memory at the behavior level. In this study, we tested the effect of subacute taurine supplementation with evaluation by the Morris water maze method. Although swim distance to find the platform of taurine-supplemented rats was significantly longer than that of control rats due to increase of swimming velocity, escape latency and the efficacy of learning and memory was comparable in both groups. These results suggest that taurine supplemented orally does not affect the learning and memory function. Taurine, 2-aminoethylsulfonic acid, is widely distributed throughout the body including the liver and heart. The roles of endogenous taurine in the liver and heart are to increase bile acid secretion by forming bile acid conjugate [2] and regulate Ca 2+ kinetics to protect and improve the heart function [17], respectively. In the brain, taurine is also abundant, especially in the hippocampus, and modulates synaptic transmission as an inhibitory neuromodulator interacting with g-aminobutyric acid type A (GABA A ) or glycine receptors [9,22]. Recent electrophysiological studies using rat brain preparations, however, have shown that taurine application induced long-lasting synaptic potentiation [3,6]. The features of this taurine-induced synaptic potentiation are similar to those of long-term potentiation (LTP) [4,19], which is a typical example of synaptic plasticity, and is thought to be a basic model for learning and memory [8], indicating that taurine is likely to be involved in learning and memory. Despite accumulation of findings on the relationship between taurine and synaptic plasticity by electrophysiological studies, the effect of taurine on learning and memory at the behavior level is complicated. Studies of acute administration of taurine indicate that it has no effect on humans [1,20] and mice [15], whereas studies investigating the subacute or chronic effect of taurine, often taken exogenously in food supplements on a daily basis, are still controversial. Sanberg and Fibiger reported that taurine impaired memory functions [16]. On the other hand, El Idrissi reported that taurine improved learning and retention in aged mice [5]. In these conflicting studies, the passive avoidance test was adopted to -Note-