Chemokine Signaling

Chemokine receptors associate with G-proteins to transmit cell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of an enzyme known as phospholipase C (PLC). PLC cleaves a molecule called phosphatidylinositol (4,5)-bisphosphate (PIP2) into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor.

Chemokine Signaling Pathway

Here we take CXCR1 and CXCR2 signaling pathways for example. CXCR1 and CXCR2 signaling pathways have been well characterized in neutrophils. While the expression of these receptors on hepatocytes has been demonstrated, the signaling pathways utilized to alter hepatocyte function are unclear. Understanding the signaling pathways utilized by CXCR1 and CXCR2 in neutrophils may offer valuable insights into how these receptors function in hepatocytes. CXCR1 and CXCR2 receptors are G-protein coupled and involve the Gαi family, specifically Gαi2 and Gαi3, as well as Gα14 and Gα16. Following G protein activation, release of the βγ subunit activates two key pathways involved in generating neutrophil end responses, namely PLCβ and PI3K. PLC-β2/β3 catalyzes the conversion of PIP2 into the second messengers DAG and IP3. DAG activates PKC and PLA2, and IP3 stimulates Ca2+ mobilization. Activation of PKC leads to translocation of p47phox to the plasma membrane, assembly of NADPH oxidase, and generation of the respiratory burst. PI3K activation catalyzes the production of PIP3. PI3K activity is central to several downstream pathways which influence neutrophil function, including Ras/Raf/MAPK and Akt, leading to neutrophil granule release, adhesion and chemotaxis, and respiratory burst (Figure 1). Additionally, expression and activation of the β2 integrin CD11b, important to neutrophil adhesion, is modulated by PKC alongside of MAPK. MAPK and PKC appear to function independently as discrete pathways, and both must be inhibited to completely abrogate integrin-dependent adhesion.

Chemokine signaling pathway

CXCR1 and CXCR2 have intertwined yet diverse roles in neutrophil activation, and receptor-specific pathways have been identified for both receptors. Using receptor-specific antibodies, it was determined that CXCR1 was uniquely linked to activation of respiratory burst through the action of phospholipase D, known to catalyze the hydrolysis of phosphatidylcholine to phosphatidic acid and choline, thus allowing phosphatidic acid (along with DAG) to activate NADPH oxidase. Matrix metalloproteinase-9 (MMP-9) is present in the tertiary granules of neutrophils and can be released through ERK1/2 and PKC dependent pathways as a result of IL-8 stimulation. Blockade of CXCR2, but not CXCR1, diminished the release of MMP-9 in IL-8 treated neutrophils, suggesting a CXCR2 dependent system.

References

Chemokine Receptor Information

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