Chemoattractant Receptor Cross-desensitization

Ali, Hydar; Richardson, Ricardo M.; Haribabu, Bodduluri; Snyderman, Ralph

doi:10.1074/jbc.274.10.6027

Cited by 248 publications

(211 citation statements)

References 51 publications

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“…We found b-dein receptors to be coupled to Ga i proteins due to their sensitivity to pertussis toxin, which confirms previously published observations [16,21]. Heterologous desensitization involving different G protein-coupled receptors is mediated by second messenger-regulated kinases such as PKC and does not require agonist occupancy [25]. On the other hand, homologous desensitization affects receptors in the agonist-occupied state and involves phosphorylation by G protein-coupled receptor kinases [26].…”

Section: Discussionsupporting

confidence: 90%

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β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

et al. 2007

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b-Defensins are natural peptide antibiotics whose immunomodulatory functions are poorly understood. In the present study, macrophages were found to migrate to human b-defensins (HBD)-1 to -4 using Ga i proteins as well as MAPK ERK, p38 and JNK as signal transducers. In addition, mast cells responded to HBD-1 to -4 with calcium fluxes as well as chemotaxis, which increased upon stimulation with IgE plus antigen or ionomycin. In contrast, human b-defensins were unable to induce migration of memory lymphocytes and dendritic cells (DC). Similar to HBD, the murine b-defensin (mBD)-8 mobilized macrophages and lacked the ability to recruit memory T cells. These findings were unexpected as CCR6 on memory T cells and DC has been previously observed to be a receptor for human b-defensins. In support of our findings, however, RBL-2H3 as well as 300.19 cells stably expressing CCR6 proved to be unresponsive to HBD-2 and -3. Intriguingly, our observation of a PKC-independent homologous desensitization between HBD-1 to -4 suggests a common receptor for HBD. In summary, chemoattraction of macrophages and mast cells is evolutionary conserved within the b-defensin family despite a considerable sequence variation and distinct antimicrobial activities. However, CCR6 is not a functional receptor for b-defensins.

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Section: Discussionsupporting

confidence: 90%

“…1E) or CCL3 (data not shown). Although desensitization can be of homologous or heterologous nature, only the latter is PKC-dependent [25,26]. As demonstrated in Fig.…”

Section: Mobilization Of Macrophagesmentioning

confidence: 99%

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

et al. 2007

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“…C hemoattractants, such as formyl containing bacterial peptides (for example, fMLP), and the complement components C3a and C5a (1)(2)(3) are among the first mediators generated at sites of bacterial infection. These chemoattractants activate leukocyte chemotaxis and cause mediator release via their interaction with cell surface G protein-coupled receptors (GPCR).…”

mentioning

confidence: 99%

“…However, very little information is available on the signaling pathways activated by C3aR. In neutrophils, both FR and C5aR couple to the same pertussis toxin (ptx)-sensitive G proteins to activate similar biological responses, such as superoxide generation and the release of proteolytic enzymes (3,6,7). The biochemical events that follow FR and C5aR activation in neutrophils include the activation of phospholipase C, phosphoinositol 3-kinase (PI3 kinase), increased association of Src family of protein kinases with p21 ras , and activation of p42/p44 mitogen-activated protein kinases (MAPK), known as extracellular signal-regulated kinases (ERKs) (6,8,9).…”

mentioning

confidence: 99%

Chemokine Production by G Protein-Coupled Receptor Activation in a Human Mast Cell Line: Roles of Extracellular Signal-Regulated Kinase and NFAT

Ali

Ahamed

Hernández-Munaín

et al. 2000

The Journal of Immunology

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Chemoattractants are thought to be the first mediators generated at sites of bacterial infection. We hypothesized that signaling through G protein-coupled chemoattractant receptors may stimulate cytokine production. To test this hypothesis, a human mast cell line (HMC-1) that normally expresses receptors for complement components C3a and C5a at low levels was stably transfected to express physiologic levels of fMLP receptors. We found that fMLP, but not C3a or C5a, induced macrophage inflammatory protein (MIP)-1β (CCL4) and monocyte chemoattractant protein-1 (CCL2) mRNA and protein. Although fMLP stimulated both sustained Ca2+ mobilization and phosphorylation of extracellular signal-regulated kinase (ERK), these responses to C3a or C5a were transient. However, transient expression of C3a receptors in HMC-1 cells rendered the cells responsive to C3a for sustained Ca2+ mobilization and MIP-1β production. The fMLP-induced chemokine production was blocked by pertussis toxin, PD98059, and cyclosporin A, which respectively inhibit Giα activation, mitgen-activated protein kinase kinase-mediated ERK phosphorylation, and calcineurin-mediated activation of NFAT. Furthermore, fMLP, but not C5a, stimulated NFAT activation in HMC-1 cells. These data indicate that chemoattractant receptors induce chemokine production in HMC-1 cells with a selectivity that depends on the level of receptor expression, the length of their signaling time, and the synergistic interaction of multiple signaling pathways, including extracellular signal-regulated kinase phosphorylation, sustained Ca2+ mobilization and NFAT activation.

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“…However this did not appear to extend to chemotaxis mediated by another agent, N-formyl-methionyl-leucyl-phenylalanine (fMLP), even though the receptors for IL-8 and fMLP are both in the G-protein-coupled receptor family. 14 …”

Section: Discussionmentioning

confidence: 99%

Differential regulation of neutrophil chemotaxis to IL‐8 and fMLP by GM‐CSF: lack of direct effect of oestradiol

et al. 2005

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Summary Neutrophils are a normal constituent of the female reproductive tract and their numbers increase in the late secretory phase of the menstrual cycle prior to menses. Several cytokines are produced in female reproductive tract tissue. In particular granulocyte–macrophage colony‐stimulating factor (GM‐CSF), a potent activator of neutrophils, is secreted in high concentrations by female reproductive tract epithelia. We previously observed that GM‐CSF synergizes strongly with interleukin‐8 (IL‐8) in enhancing chemotaxis of neutrophils. Thus we investigated whether pretreatment of neutrophils with GM‐CSF would prime subsequent chemotaxis to IL‐8 in the absence of GM‐CSF. Surprisingly, a 3‐hr pulse of GM‐CSF severely diminished chemotaxis to IL‐8, whereas N‐formyl‐methyl‐leucyl‐phenylalanine (fMLP)‐mediated chemotaxis was retained. Conversely, when cells were incubated without GM‐CSF they retained IL‐8‐mediated migration but lost fMLP chemotaxis. These changes in chemotaxis did not correlate with expression of CXCR1, CXCR2 or formyl peptide receptor. However, IL‐8‐mediated phosphorylation of p44/42 mitogen‐activated protein kinase was greatly reduced in neutrophils that no longer migrated to IL‐8, and was diminished in cells that no longer migrated to fMLP. Oestradiol, which is reported by some to exert an anti‐inflammatory effect on neutrophils, did not change the effects of GM‐CSF. These data suggest that neutrophil function may be altered by cytokines such as GM‐CSF through modulation of signalling and independently of surface receptor expression.

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Chemoattractant Receptor Cross-desensitization

Cited by 248 publications

References 51 publications

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

Chemokine Production by G Protein-Coupled Receptor Activation in a Human Mast Cell Line: Roles of Extracellular Signal-Regulated Kinase and NFAT

Differential regulation of neutrophil chemotaxis to IL‐8 and fMLP by GM‐CSF: lack of direct effect of oestradiol

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