Interferon-γ Elicits a G-Protein-Dependent Ca2+ Signal in Human Neutrophils after Depletion of Intracellular Ca2+ Stores

Aas, Vigdis; Larsen, Kristin; Iversen, Jens-Gustav

doi:10.1016/s0898-6568(98)00040-0

Cited by 20 publications

(19 citation statements)

References 48 publications

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“…IFN-␥ induced a rapid and sharp increase in [Ca 2ϩ ] i in a dose-dependent manner ( Fig. 2A), similar to results reported previously with other cell types (28,29). Autophosphorylation of CaMKII occurs in situ accompanying enzymatic activation and renders CaMKII Ca 2ϩ -independent, and the Ca 2ϩ -independent activity is used to assess activation of CaMKII (21).…”

Section: Resultssupporting

confidence: 88%

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Requirement of Ca²⁺and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ

Nair

DaFonseca

Tjernberg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

108

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In response to IFN-γ, the latent cytoplasmic protein signal transducers and activators of transcription 1 (Stat1) becomes phosphorylated on Y701, dimerizes, and accumulates in the nucleus to activate transcription of IFN-γ-responsive genes. For maximal gene activation, S727 in the transcription activation domain of Stat1 also is inducibly phosphorylated by IFN-γ. We previously purified a group of nuclear proteins that interact specifically with the Stat1 transcription activation domain. In this report, we identified one of them as the multifunctional Ca 2+ /calmodulin-dependent kinase (CaMK) II. We demonstrate that IFN-γ mobilizes a Ca 2+ flux in cells and activates CaMKII. CaMKII can interact directly with Stat1 and phosphorylate Stat1 on S727 in vitro . Inhibition of Ca 2+ flux or CaMKII results in a lack of S727 phosphorylation and Stat1-dependent gene activation, suggesting in vivo phosphorylation of Stat1 S727 by CaMKII. Thus two different cellular signaling events, IFN-γ receptor occupation and Ca 2+ flux, are required for Stat1 to achieve maximal transcriptional activation through regulation of phosphorylation.

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Section: Resultssupporting

confidence: 88%

“…IFN-␥ has been shown to elicit a Ca 2ϩ flux in certain cell types (27)(28)(29), suggesting a possible involvement of Ca 2ϩ flux in IFN-␥ signaling. However, its physiological consequence was not clear.…”

mentioning

confidence: 99%

Requirement of Ca²⁺and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ

Nair

DaFonseca

Tjernberg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

108

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“…Inhibitors were titrated in preliminary experiments to determine the optimal inhibitory dose. Pertussis toxin (G i protein inhibitor [1,42]) was obtained from Sigma Chemical Co.. PP2 (Src family tyrosine kinase inhibitor [45]), PD098059 (ERK inhibitor [18,36]), wortmannin (phosphatidylinositol 3-kinase inhibitor [19]), SB203580 (p38 MAP kinase inhibitor [54]), and AG490 (Janus kinase inhibitor [38]) were from Calbiochem, La Jolla, Calif. Where necessary, inhibitors were diluted in dimethyl sulfoxide (Sigma Chemical Co.). Diluted dimethyl sulfoxide had no effect on spontaneous neutrophil apoptosis (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Toxoplasma gondiiInduces Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Secretion by Human Fibroblasts: Implications for Neutrophil Apoptosis

Channon¹,

Miselis²,

Minns³

et al. 2002

Infect Immun

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Human neutrophils are rescued from apoptosis following incubation with once-washed, fibroblast-derived Toxoplasma gondii tachyzoites. Both infected and uninfected neutrophils are rescued, implicating a soluble mediator. In this study we investigated the origin and identity of this soluble mediator. Neutrophils were incubated either with purified tachyzoites or with conditioned medium derived from T. gondii-infected human fibroblasts. Conditioned medium was found to be a potent stimulus that delayed neutrophil apoptosis up to 72 h, whereas purified and extensively washed tachyzoites had no effect. Delayed apoptosis correlated with up-regulation of the neutrophil antiapoptotic protein, Mcl-1, and the neutrophil interleukin 3 receptor ␣ subunit (IL-3R␣), suggesting a role for granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF and granulocyte colony-stimulating factor (G-CSF) were measurable in conditioned medium by enzymelinked immunosorbent assay. Neutralizing antibodies to GM-CSF and G-CSF were additive in abrogating delayed neutrophil apoptosis induced by conditioned medium. Inhibitors of Src family tyrosine kinases, G i proteins, phosphatidylinositol 3-kinase, p44 erk1 and p42 erk2 mitogen-activated protein kinases, and Jak2 kinases partially attenuated the effect of conditioned medium, consistent with a role for G-CSF and/or GM-CSF. Hence, delayed neutrophil apoptosis is mediated by GM-CSF and G-CSF secreted by T. gondii-infected human fibroblasts. This enhanced neutrophil survival may contribute to the robust proinflammatory response elicited in the T. gondii-infected host.

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“…IFN-␥ is a broadly acting cytokine whose actions include up-regulation of the respiratory burst, neutrophil and monocyte activation, and degranulation among many others (Aas et al, 1999;Gaviria et al, 1999;Kullberg et al, 1993). As a T helper 1 cytokine, IFN-␥ is thought to play a primary role in host defenses against intracellular microbes.…”

mentioning

confidence: 99%

Kinetics of CD11b/CD18 Up-Regulation During Infection with the Agent of Human Granulocytic Ehrlichiosis in Mice

Borjesson

Simon

Hodzic

et al. 2002

Laboratory Investigation

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SUMMARY:The agent of human granulocytic ehrlichiosis (aoHGE) is a tick-borne, obligate intracellular, granulocytotropic bacterium able to infect numerous host species. Given its unique niche and the leukopenia often noted with infection, we investigated the effect of acute aoHGE infection on neutrophil activation by evaluating surface expression of the ␤2 integrin CD11b/CD18 in a mouse model using FACS analysis. Infection resulted in neutrophil activation with up-regulation of CD11b/CD18 in multiple strains of mice, however, hematologic analysis showed no apparent role for CD11b/CD18 in mediating peripheral leukopenia. Because IFN-␥ is an important cytokine during granulocytic ehrlichiosis and is known to activate leukocytes, we investigated the potential role of IFN-␥ in CD11b/CD18 up-regulation. Neutrophils from IFN-␥ knock-out mice became activated during aoHGE infection, however, the kinetics of activation differed from wild-type mice. In addition, activation correlated directly with the presence of bacteria because neutrophils with large intracytoplasmic morula also expressed higher levels of CD11b/CD18. CD11b/CD18 seemed to be critical to early bacterial clearance and killing in vivo because infection of mice with targeted genetic disruption of CD11b/CD18 resulted in an initial increase in bacterial burden compared with wild-type mice. Similarly, in vitro culture of neutrophils from infected CD11b/CD18 knock-out mice resulted in a marked increase in bacterial proliferation compared with congenic controls. The data support crucial roles of CD11b/CD18 and IFN-␥-mediated cell activation as mechanisms that limit bacterial replication. (Lab Invest 2002, 82:303-311).

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Interferon-γ Elicits a G-Protein-Dependent Ca2+ Signal in Human Neutrophils after Depletion of Intracellular Ca2+ Stores

Cited by 20 publications

References 48 publications

Requirement of Ca²⁺and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ

Requirement of Ca²⁺and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ

Toxoplasma gondiiInduces Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Secretion by Human Fibroblasts: Implications for Neutrophil Apoptosis

Kinetics of CD11b/CD18 Up-Regulation During Infection with the Agent of Human Granulocytic Ehrlichiosis in Mice

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Interferon-γ Elicits a G-Protein-Dependent Ca2+ Signal in Human Neutrophils after Depletion of Intracellular Ca2+ Stores

Cited by 20 publications

References 48 publications

Requirement of Ca2+and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ

Requirement of Ca2+and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ

Toxoplasma gondiiInduces Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Secretion by Human Fibroblasts: Implications for Neutrophil Apoptosis

Kinetics of CD11b/CD18 Up-Regulation During Infection with the Agent of Human Granulocytic Ehrlichiosis in Mice

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Requirement of Ca²⁺and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ

Requirement of Ca²⁺and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ