C5a differentially stimulates the ERK1/2 and p38 MAPK phosphorylation through independent signaling pathways to induced chemotactic migration in RAW264.7 macrophages

Chiou, Wen-Fei; Tsai, Hwei-Ru; Yang, Liming; Tsai, Wei‐Jern

doi:10.1016/j.intimp.2004.05.017

Cited by 42 publications

(33 citation statements)

References 32 publications

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“…The c-Raf kinase therefore represents an important link between Akt and ERK1/2 MAPK signaling pathways. Another group has described recently that, in macrophages, C5a induces PI3K/Akt activation, leading to downstream activation of ERK1/2 (27). Our group demonstrated earlier rapid phosphorylation of Akt in neutrophils upon stimulation with C5a (2).…”

Section: Activation Of the Pi3k/akt Signaling Pathway In Neutrophils supporting

confidence: 56%

The Phosphatidylinositol 3-Kinase Signaling Pathway Exerts Protective Effects during Sepsis by Controlling C5a-Mediated Activation of Innate Immune Functions

Wrann

Tabriz

Barkhausen

et al. 2007

The Journal of Immunology

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The PI3K/Akt signaling pathway has been recently suggested to have controversial functions in models of acute and chronic inflammation. Our group and others have reported previously that the complement split product C5a alters neutrophil innate immunity and cell signaling during the onset of sepsis and is involved in PI3K activation. We report in this study that in vivo inhibition of the PI3K pathway resulted in increased mortality in septic mice accompanied by strongly elevated serum levels of TNF-α, IL-6, MCP-1, and IL-10 during sepsis as well as decreased oxidative burst activity in blood phagocytes. PI3K inhibition in vitro resulted in significant increases in TLR-4-mediated generation of various proinflammatory cytokines in neutrophils, whereas the opposite effect was observed in PBMC. Oxidative burst and phagocytosis activity was significantly attenuated in both neutrophils and monocytes when PI3K activation was blocked. In addition, PI3K inhibition resulted in strongly elevated TLR-4-mediated generation of IL-1β and IL-8 in neutrophils when these cells were costimulated with C5a. C5a-induced priming effects on neutrophil and monocyte oxidative burst activity as well as C5a-induced phagocytosis in neutrophils were strongly reduced when PI3K activation was blocked. Our data suggest that the PI3K/Akt signaling pathway controls various C5a-mediated effects on neutrophil and monocyte innate immunity and exerts an overall protective effect during experimental sepsis.

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Section: Activation Of the Pi3k/akt Signaling Pathway In Neutrophils supporting

confidence: 56%

The Phosphatidylinositol 3-Kinase Signaling Pathway Exerts Protective Effects during Sepsis by Controlling C5a-Mediated Activation of Innate Immune Functions

Wrann

Tabriz

Barkhausen

et al. 2007

The Journal of Immunology

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“…In the case of C5aR, this is rather surprising as it is known to be primarily located at the cell surface whereas C5L2 is known to be primarily intracellular (manuscript in preparation). The C5aR can transduce signals via phosphorylation of p44/42 MAPK, AKT and p38 MAPK (Monsinjon et al 2003, Chiou et al 2004, Riedemann et al 2004a. Our data are consistent with these findings and also indicate that C5adR is not an activator of these signals, presumably due to its low activity at the C5aR.…”

Section: Discussionsupporting

confidence: 90%

Complement C5a receptors in the pituitary gland: expression and function

Francis

Lewis²,

Monk³

et al. 2008

Journal of Endocrinology

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Communication between the immune and endocrine system is important for the control of inflammation that is primarily mediated through the hypothalamic-pituitary-adrenal axis. The innate immune system rapidly responds to pathogens by releasing complement proteins that include the anaphylatoxins C3a and C5a. We previously reported the existence of C3a receptors in the anterior pituitary gland and now describe the presence of C5a receptors in the gland. C5a and its less active derivative (C5adR) can bind to its own receptor and to another receptor called C5L2. Using RT-PCR and immunocytochemistry, C5a receptors and C5L2 were demonstrated in the rat anterior pituitary gland and in several rodent anterior pituitary cell lines. Western blotting analysis showed that C5a stimulated the phosphorylation of MAPK and AKT but not p38; C5adR on the other hand, had no effect on any of the signal molecules investigated. The effects of C5a and C5adR on the secretion of the inflammatory molecule, macrophage migration inhibitory factor (MIF) were investigated by ELISA. Both compounds showed a dose-dependent inhibition of MIF release, 30-40% inhibition at around 35-70 nM agonist with IC50 values of around 20 nM. C5a and C5adR also stimulated ACTH secretion (up to 25%) from AtT-20DV16 cells. These data show that functional C5a receptors (C5a and C5L2) are present in the anterior pituitary gland and they may play a role in dampening down inflammation by inhibiting the release of MIF and stimulating the release of ACTH.

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“…PLC␤2 is a cytosolic protein (12,27). To hydrolyze its membrane-localized substrate, phosphatidylinositol 4,5-bisphosphate, PLC␤2 must first be translocated to the membrane.…”

Section: Discussionmentioning

confidence: 99%

“…To hydrolyze its membrane-localized substrate, phosphatidylinositol 4,5-bisphosphate, PLC␤2 must first be translocated to the membrane. Indeed, agonist-stimulated PLC␤2 translocation has been demonstrated in both neu- trophils and macrophages (12,28). However, the underlying mechanisms for PLC␤2 translocation have not yet been defined.…”

Section: Discussionmentioning

confidence: 99%

WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes

Sun¹,

Smrcka

Chen

2013

Journal of Biological Chemistry

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Background: It remains unclear how G␤␥ regulates diverse effectors in cells. Results: WDR26 exists in oligomers. It simultaneously binds both G␤␥ and PLC␤2 to enhance PLC␤2 membrane translocation and activation by G␤␥ in leukocytes. Conclusion: WDR26 functions as a scaffolding protein to promote G␤␥-mediated PLC␤2 activation. Significance: These findings uncover a novel mechanism of regulating G␤␥ signaling through a scaffolding protein.

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C5a differentially stimulates the ERK1/2 and p38 MAPK phosphorylation through independent signaling pathways to induced chemotactic migration in RAW264.7 macrophages

Cited by 42 publications

References 32 publications

The Phosphatidylinositol 3-Kinase Signaling Pathway Exerts Protective Effects during Sepsis by Controlling C5a-Mediated Activation of Innate Immune Functions

The Phosphatidylinositol 3-Kinase Signaling Pathway Exerts Protective Effects during Sepsis by Controlling C5a-Mediated Activation of Innate Immune Functions

Complement C5a receptors in the pituitary gland: expression and function

WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes

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