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Xythalis, Demetra; Frewin, Mary Beth; Gudewicz, Paul W.

doi:10.1023/a:1014836211643

Cited by 15 publications

(2 citation statements)

References 25 publications

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“…A crucial initial step in this is the recruitment of neutrophils to sites of infection and inflammation by a process known as chemotaxis. A number of studies have reported that the extracellular signal-regulated protein kinase (ERK) 1 1 and ERK2 modules are involved in regulating neutrophil chemotaxis (3)(4)(5)(6)(7). These studies showed that PD98059, a specific inhibitor of mitogen-activated protein (MAP) kinase/ERK kinase (MEK)1 and MEK2, the immediate upstream regulators of ERK1 and ERK2, inhibited chemotaxis in response to fMLP or IL8.…”

mentioning

confidence: 99%

Characterization of the MEK5-ERK5 Module in Human Neutrophils and Its Relationship to ERK1/ERK2 in the Chemotactic Response

Hii

Anson

Costabile

et al. 2004

Journal of Biological Chemistry

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The role of the extracellular signal-regulated kinase (ERK) 1 and ERK2 in the neutrophil chemotactic response remains to be identified since a previously used specific inhibitor of MEK1 and MEK2, PD98059, that was used to provide evidence for a role of ERK1 and ERK2 in regulating chemotaxis, has recently been reported to also inhibit MEK5. This issue is made more critical by our present finding that human neutrophils express mitogen-activated protein (MAP) kinase/ERK kinase (MEK)5 and ERK5 (Big MAP kinase), and that their activities were stimulated by the bacterial tripeptide, formyl methionyl-leucyl-phenylalanine (fMLP). Dose response studies demonstrated a bell-shaped profile of fMLP-stimulated MEK5 and ERK5 activation, but this was left-shifted when compared with the profile of fMLP-stimulated chemotaxis. Kinetics studies demonstrated increases in kinase activity within 2 min, peaking at 3-5 min, and MEK5 activation was more persistent than that of ERK5. There were some similarities as well as differences in the pattern of activation between fMLP-stimulated ERK1 and ERK2, and MEK5-ERK5 activation. The up-regulation of MEK5-ERK5 activities was dependent on phosphatidylinositol 3-kinase. Studies with the recently described specific MEK inhibitor, PD184352, at concentrations that inhibited ERK1 and ERK2 but not ERK5 activity demonstrate that the ERK1 and ERK2 modules were involved in regulating fMLPstimulated chemotaxis and chemokinesis. Our data suggest that the MEK5-ERK5 module is likely to regulate neutrophil responses at very low chemoattractant concentrations whereas at higher concentrations, a shift to the ERK1/ERK2 and p38 modules is apparent.Neutrophils, while playing an important role in host defense by killing microbial pathogens, are also responsible for tissue destruction in inflammatory conditions such as rheumatoid arthritis (1) and cystic fibrosis (2). A crucial initial step in this is the recruitment of neutrophils to sites of infection and inflammation by a process known as chemotaxis. A number of studies have reported that the extracellular signal-regulated protein kinase (ERK) 1 1 and ERK2 modules are involved in regulating neutrophil chemotaxis (3-7). These studies showed that PD98059, a specific inhibitor of mitogen-activated protein (MAP) kinase/ERK kinase (MEK)1 and MEK2, the immediate upstream regulators of ERK1 and ERK2, inhibited chemotaxis in response to fMLP or IL8. However, PD98059 and another specific MEK1/MEK2 inhibitor, UO126, have recently been reported to also inhibit MEK5, the upstream regulator of ERK5 (8, 9). This therefore creates some doubt as to whether the previous conclusion is valid and whether the MEK5-ERK5 module could also be involved in regulating the chemotactic response.ERK5 or Big MAP kinase (BMK) is a recently described stress-activated MAP kinase (10, 11). This kinase is similar in many aspects to ERK1 and ERK2, but has a unique loop 12 domain within the kinase region, which is followed by an unusually long C terminus. Although murine tissues have been reported...

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mentioning

confidence: 99%

Characterization of the MEK5-ERK5 Module in Human Neutrophils and Its Relationship to ERK1/ERK2 in the Chemotactic Response

Hii

Anson

Costabile

et al. 2004

Journal of Biological Chemistry

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“…Some of them are also receptors for bacteria invasions. It has been reported that α5β1 integrin ligation on an extracellular matrix fibronectin fragment in human PMNLs inhibited chemotaxis toward IL-8 and then mediated MAPK signaling [43]. Interestingly, the linkage between actin and integrins plays a key role in actin polymerization and organization to promote adhesion and other signal pathways [44].…”

Section: Discussionmentioning

confidence: 99%

Secreted MbovP0145 Promotes IL-8 Expression through Its Interactive β-Actin and MAPK Activation and Contributes to Neutrophil Migration

Zhang

et al. 2021

Pathogens

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Mycoplasma bovis (M. bovis) is an important pathogen of cattle responsible for huge economic losses in the dairy and beef industries worldwide. The proteins secreted by M. bovis are mainly related to its adhesion, invasion, virulence, and intracellular survival and play a role in mycoplasma–host interactions. In our previous study, we found MbovP0145, a secreted protein present in the M. bovis secretome, but little is known about its function. In this study, we assessed the inflammatory characteristics and underlined mechanism of this inflammation of recombinant MbovP0145 (rMbovP0145). For this, bovine lung epithelial cells (EBL) were stimulated by rMbovP0145 to see the IL-8 production in a time- and dose-dependent manner. We observed that rMbovP0145 increased the production of IL-8 via ERK1/2 and P38 pathway activation. Further, the effect of the M. bovis ΔMbov_0145 mutant and its complementary strain on IL-8 mRNA expression was also confirmed. A pulldown assay of the GST-tagged MbovP0145 protein with mass spectrometry demonstrated that β-actin could specifically interact with rMbovP0145 to mediate the IL-8 signaling. As knockdown of β-actin expression with RNA interference in EBL cells decreased the mRNA expression of IL-8 and the phosphorylated ERK1/2 and P38 proteins, whereas disrupted actin polymerization by cytochalasin D led to a significantly higher IL-8 expression and MAPK phosphorylation in rMbovP0145-stimulated cells. Compared to M. bovis HB0801 and its complementary strain, the culture supernatant of EBL cells infected with the M. bovis ΔMbov_0145 mutant induced less neutrophil migration to the lower chamber in a transwell system. In conclusion, MbovP0145 promoted IL-8 expression by interacting with β-actin through activation of the MAPK pathway, thus contributing to neutrophil migration.

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