Inhibition of cytokinechemokine production After establishing the

Inhibition of cytokinechemokine production After establishing the inhibitory effect of hemin on iNOS expression and NO production, we investigated whether hemin also would suppress the production of other inflammatory mediators, i. e. cytokines and chemo kines, produced by IL 1b stimulated human astrocytes. Previously, we found that IL 1b activated human astro cytes release TNF a and CXCL10. Following hemin pretreatment, IL 1b induced TNF a and CXCL10 pro duction was down regulated and this inhibi tion was blocked significantly by SnPP suggesting the involvement of HO. Discussion In the current study, we demonstrated that hemin robustly induces HO 1 expression in human astrocytes and that pretreatment with hemin significantly inhibited IL 1b induced iNOS expression, NO production, and TNF a as well as CXCL10 release.

Furthermore, we showed that this inhibitory effect was markedly reversed by the HO activity inhibitor tin protoporphyrin, suggesting the invol vement of an HO mediated mechanism. IL 1b induced NO production is known to be p38 MAPK dependent, and we found that hemin treatment Inhibitors,Modulators,Libraries down regulated IL 1b induced p38 MAPK, suggesting the involvement of this intracellular signaling pathway in hemins inhibitory action. Interleukin 1b activates astrocytes robustly to pro duce inflammatory mediators including cytokines, chemo kines, and NO, which may contribute to autocrine and paracrine effects on neighboring neuronal and glial cells. Nitric oxide is one of the stimuli known to induce HO 1, which exerts a possible feedback inhibi tion on NO, as seen in this study.

The role of HO 1 under different experimental para digms and disease conditions Inhibitors,Modulators,Libraries has been found to be either beneficial or damaging and its protective func tion is debatable. Due to inflammatory mediator pro duction by IL 1b activated astrocytes leading to potential harmful consequences, our Inhibitors,Modulators,Libraries hypothesis was that hemin induction of anti inflammatory HO 1 expression in IL 1b activated astrocytes would be ben eficial. The results of this study support the notion that hemin inhibits IL 1b induced Inhibitors,Modulators,Libraries iNOS expression and NO production in human astrocytes and are in agreement with findings of others using cell types not found within the nervous system. The interplay and negative feedback interaction between HO 1 and iNOS that we found in this study has been observed in the study of glomerulonephritis.

This phenom enon has also been suggested to involve Inhibitors,Modulators,Libraries a reduction of the available heme pool for de novo iNOS synth esis, CO interacting with iNOS heme moiety and iron down regulation of iNOS transcription. In this study we also confirmed the finding that NO production is dependent on p38 MAPK. The down regulation of p38 MAPK by hemin pretreatment sug gests involvement of the p38 MAPK signaling pathway in the inhibitory effect of hemin on IL 1b induced NO production. In the murine macrophage cell line RAW264.

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