The Atypical Zeta (ζ) Isoform of Protein Kinase C Regulates CD11b/CD18 Activation in Human Neutrophils

Chakrabarti, Subhadeep; Patel, Kamala D.

doi:10.1080/10739680801949732

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…LFA-1 clustering induced by the chemokine CCL-21 was markedly reduced by a PKC-f pseudosubstrate inhibitory peptide (Giagulli et al 2004). For neutrophils, a similar approach was used by Chakrabarti and Patel (2008), who examined IL-8-induced Mac-1 clustering with or without the same PKC-f inhibitory peptide. By blocking PKC-f with that method, Mac-1 clustering was prevented (Chakrabarti and Patel 2008).…”

Section: Adhesion Strengthening and Crawlingmentioning

confidence: 99%

“…For neutrophils, a similar approach was used by Chakrabarti and Patel (2008), who examined IL-8-induced Mac-1 clustering with or without the same PKC-f inhibitory peptide. By blocking PKC-f with that method, Mac-1 clustering was prevented (Chakrabarti and Patel 2008). These findings suggest the involvement of PKC isoforms in outside-in signaling, because clustering of b 2 -integrins in neutrophils is mediated via outside-in signaling involving Src family kinases (Mócsai et al 1999(Mócsai et al , 2006Piccardoni et al 2004).…”

Section: Adhesion Strengthening and Crawlingmentioning

confidence: 99%

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Protein Kinase C Isoforms in Neutrophil Adhesion and Activation

Bertram

Ley

2011

Arch. Immunol. Ther. Exp.

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Neutrophils are the first line of defense against bacterial and mycotic pathogens. In order to reach the pathogens, neutrophils need to transmigrate through the vascular endothelium and migrate to the site of infection. Defense strategies against pathogens include phagocytosis, production and release of oxygen radicals through the oxidative burst, and degranulation of antimicrobial and inflammatory molecules. Protein kinase C (PKC)-δ is required for full assembly of NADPH oxidase and activation of the respiratory burst. Neutrophils also express PKC-α and -β, which may be involved in adhesion, degranulation and phagocytosis, but the evidence is not conclusive yet. This review focuses on the potential impact of protein kinase C isoforms on neutrophil adhesion and activation.

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Section: Adhesion Strengthening and Crawlingmentioning

confidence: 99%

Section: Adhesion Strengthening and Crawlingmentioning

confidence: 99%

Protein Kinase C Isoforms in Neutrophil Adhesion and Activation

Bertram

Ley

2011

Arch. Immunol. Ther. Exp.

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“…Once adherent, the ligand-bound integrins initiate outside-in signaling events that involve SYK (10) and Src kinases (11,12). Using pseudosubstrate inhibition, the atypical isoform protein kinase C (PKC)-z has been implicated in outside-in signaling downstream of the b 2 integrin Mac-1 (13), but Mac-1 has no known role in neutrophil adhesion under flow. The functional role of PKC has not yet been investigated in the context of neutrophil adhesion to the vascular endothelium (14).…”

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confidence: 99%

Protein Kinase C-θ Is Required for Murine Neutrophil Recruitment and Adhesion Strengthening under Flow

Bertram

Zhang

Vietinghoff

et al. 2012

The Journal of Immunology

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Protein kinase C (PKC)-θ is involved in T cell activation via regulating the avidity of the β2 integrin LFA-1 in the immunological synapse. LFA-1 also mediates leukocyte adhesion. To investigate the role of PKC-θ in neutrophil adhesion, we performed intravital microscopy in cremaster venules of mice reconstituted with bone marrow from LysM-GFP+ (wild-type [WT]) and PKC-θ gene-deficient (Prkcq−/−) mice. Following stimulation with CXCL1, both WT and Prkcq−/− cells became adherent. Although most WT neutrophils remained adherent for at least 180 s, 50% of Prkcq−/− neutrophils were detached after 105 s and most by 180 s. Upon CXCL1 injection, rolling of all WT neutrophils stopped for 90 s, but rolling of Prkcq−/− neutrophils started 30 s after CXCL1 stimulation. A similar neutrophil adhesion defect was seen in vitro, and spreading of Prkcq−/− neutrophils was delayed. Prkcq−/− neutrophil recruitment was impaired in fMLP-induced transmigration into the cremaster muscle, thioglycollate-induced peritonitis, and LPS-induced lung injury. We conclude that PKC-θ mediates integrin-dependent neutrophil functions and is required to sustain neutrophil adhesion in postcapillary venules in vivo. These findings suggest that the role of PKC-θ in outside–in signaling following engagement of neutrophil integrins is relevant for inflammation in vivo.

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“…Several studies have shown that treatment of isolated human neutrophils with ζ-PKC pseudosubstrate inhibitor peptide significantly attenuates IL-8 induced adhesion [27]. Specifically, results from Chakrabarti et al point to a roll for ζ-PKC in the regulation of the β2-integrin CD11b (also known as MAC-1) affinity and avidity [74]. We take great interest in the finding that ζ-PKC attenuates IL-8 mediated neutrophil chemotaxis in vitro with no apparent effect on MARCKS phosphorylation and plan to perform follow up investigations.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Neutrophil Migration Requires Protein Kinase C-Delta (δ-PKC)-Mediated Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) Phosphorylation

et al. 2014

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Dysregulated release of neutrophil reactive oxygen species and proteolytic enzymes contributes to both acute and chronic inflammatory diseases. Therefore, molecular regulators of these processes are potential targets for new anti-inflammatory therapies. We have shown previously that MARCKS (Myristoylated Alanine Rich C-Kinase Substrate), a well-known PKC substrate protein, is a key regulator of neutrophil functions. In the current study we investigate the role of PKC-mediated MARCKS phosphorylation in neutrophil migration and adhesion in vitro. We report that treatment of human neutrophils with the δ-PKC inhibitor rottlerin significantly attenuates fMLF induced MARCKS phosphorylation (IC50 = 5.709 μM), adhesion (IC50 = 8.4 uM) and migration (IC50 = 6.7 uM); while α-, β- and ζ-PKC inhibitors had no significant effect. We conclude that δ-PKC mediated MARCKS phosphorylation is essential for human neutrophil migration and adhesion in vitro. These results implicate δ-PKC mediated MARCKS phosphorylation as a key step in the inflammatory response of neutrophils.

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The Atypical Zeta (ζ) Isoform of Protein Kinase C Regulates CD11b/CD18 Activation in Human Neutrophils

Abstract: These data suggest that PKCzeta is a negative regulator of Mac-1 affinity and a positive regulator of Mac-1 avidity. Further, Mac-1 avidity is more important than increased affinity alone in regulating neutrophil firm adhesion.

Cited by 10 publications

References 40 publications

Protein Kinase C Isoforms in Neutrophil Adhesion and Activation

Protein Kinase C Isoforms in Neutrophil Adhesion and Activation

Protein Kinase C-θ Is Required for Murine Neutrophil Recruitment and Adhesion Strengthening under Flow

In Vitro Neutrophil Migration Requires Protein Kinase C-Delta (δ-PKC)-Mediated Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) Phosphorylation

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