Intracellular protein phosphorylation in murine peritoneal macrophages in response to bacterial lipopolysaccharide (LPS): Effects of kinase-inhibitors and LPS-induced tolerance

Nakano, Masayasu; Saito, Shinji; Nakano, Yasunobu; Yamasu, Hiromi; Matsuura, Motohiro; Shinomiya, Hiroto

doi:10.1016/s0171-2985(11)80344-x

Cited by 35 publications

(15 citation statements)

References 31 publications

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“…The physiological relevance of these kinase signals to macrophage functions has been proven by their crucial roles in iNOS and COX-2 induction (8, 38 -40, 51). Recent studies further suggested that ERK (28), p38 MAPK (28,52), and PKC (53,54) were responsible for the enhanced trans-activation of NF-B via an IB degradation-independent mechanism. In this study we found that the stimulating effects of LPS on p38 MAPK and PKC, but not on ERK and JNK, were also attenuated by C 2 -ceramide.…”

Section: Discussionmentioning

confidence: 99%

Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors

Hsu

Chi

Huang

et al. 2001

The Journal of Immunology

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The goal of this study was to elucidate whether triggering the sphingomyelin pathway modulates LPS-initiated responses. For this purpose we investigated the effects of N-acetylsphingosine (C2-ceramide) on LPS-induced production of NO and PGE2 in murine RAW 264.7 macrophages and explored the signaling pathways involved. We found that within a range of 10–50 μM, C2-ceramide inhibited LPS-elicited NO synthase and cyclooxygenase-2 induction accompanied by a reduction in NO and PGE2 formation. By contrast, a structural analog of C2-ceramide that does not elicit functional activity, C2-dihydroceramide, did not affect the LPS response. The nuclear translocation and DNA binding study revealed that ceramide can inhibit LPS-induced NF-κB and AP-1 activation. The immunocomplex kinase assay indicated that IκB kinase activity stimulated by LPS was inhibited by ceramide, which concomitantly reduced the IκBα degradation caused by LPS within 1–6 h. In concert with the decreased cytosolic p65 protein level, LPS treatment resulted in rapid nuclear accumulation of NF-κB subunit p65 and its association with the cAMP-responsive element binding protein. Ceramide coaddition inhibited all the LPS responses. In addition, LPS-induced PKC and p38 mitogen-activated protein kinase activation were overcome by ceramide. In conclusion, we suggest that ceramide inhibition of LPS-mediated induction of inducible NO synthase and cyclooxygenase-2 is due to reduction of the activation of NF-κB and AP-1, which might result from ceramide’s inhibition of LPS-stimulated IκB kinase, p38 mitogen-activated protein kinase, and protein kinase C.

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Section: Discussionmentioning

confidence: 99%

Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors

Hsu

Chi

Huang

et al. 2001

The Journal of Immunology

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“…ance [35,36]. More recent studies have shown that an inhibitor of phosphatase 1 and 2A, OA [37], inhibits the hyporesponsive state.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-κB translocation and requires protein synthesis

Fox

Leingang

1998

Journal of Leukocyte Biology

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Activation of the resident hepatic macrophage population, Kupffer cells, leads to production of mediators that initiate, potentiate, and modulate hepatic injury. Recent studies have shown that activation of the pluripotent transcription factor nuclear factor-B (NF-B) is an important step in the induction of inflammatory cytokines, chemokines, growth factors, cell adhesion proteins, and cytokine receptors, thus efforts have been focused to modulate its activity. A common observation in diverse experimental systems is that oxidant stress activates NF-B and antioxidant drugs prevent activation and subsequent inflammatory gene transcription. However, we have recently shown that the inhibitory effect of N-acetylcysteine (NAC) is independent of its role as a substrate of glutathione synthesis and NAC can inhibit Kupffer cell activation at points beyond the initiation of activation. The goal of this study was to characterize the mechanism for NAC-mediated inhibition of Kupffer cell activation. We show for the first time that this process requires a cellular synthetic response to prevent both NF-B and tumor necrosis factor ␣ (TNF-␣) mRNA activation. Furthermore, NACmediated inhibition occurs after degradation of IB-␣ and nuclear translocation of NF-B. These data suggest that inhibition of Kupffer cell activation by NAC is a nuclear event and offers a potential approach to modulate Kupffer cell activation during hepatic injury.

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“…The first transmembrane signaling mechanism after activation of cells by LPS is a rapid tyrosine phosphorylation of a number of distinct proteins including mitogen‐activated and other protein kinases. 30,32 The next step in the cytoplasmic nuclear transduction pathways in LPS‐activated cells is the mobilization of the nuclear transcription factor ‐κB (NF‐κB). The LPS‐stimulated induction of NF‐κB in the nucleus is essential for expression of cytokine genes, such as TNF, IL‐1, and IL‐6, 33 with the consequent transcription and translation of these genes and finally the local or systemic appearance of cytokines after confrontation of an organism with LPS.…”

Section: Molecular Mechanisms Of Endotoxin Tolerancementioning

confidence: 99%

Tolerance to Pyrogens

Zeisberger

Roth

1998

Annals of the New York Academy of Sciences

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In humans or experimental animals, the repeated confrontation with lipopolysaccharides (LPS) from gram-negative bacteria, but not with muramyl dipeptide (MDP) from gram-positive bacteria, leads to attenuation of almost all pathophysiologic effects mediated by proinflammatory cytokines. Our experiments in guinea pigs and rats demonstrate that attenuation of the febrile response during the development of LPS tolerance is associated with a reduced production of cytokines rather than a decrease in responsiveness to cytokines. Cross-tolerance experiments demonstrate that different stimuli influencing LPS-induced tumor necrosis factor (TNF) release and nitric oxide (NO) synthesis can modify the development of tolerance. On the other hand, the lack of cross-tolerance between LPS and MDP indicates that MDP can activate the cytokine cascade and induce the febrile response in animals tolerant to LPS. This may indicate distinct receptors and signal pathways for LPS and MDP, leading to activation of the cytokine cascade. LPS tolerance has also been demonstrated in ex vivo and in vitro studies. In cultures of monocytes, diminished synthesis of TNF and NO reported after LPS restimulation could be prevented and reversed by interferon and granulocyte-macrophage colony-stimulating factor. These findings add an additional hypothesis in tolerance development.

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Intracellular protein phosphorylation in murine peritoneal macrophages in response to bacterial lipopolysaccharide (LPS): Effects of kinase-inhibitors and LPS-induced tolerance

Cited by 35 publications

References 31 publications

Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors

Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors

Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-κB translocation and requires protein synthesis

Tolerance to Pyrogens

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