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Involvement of calmodulin and calmodulin kinase II in tumor necrosis factor alpha-induced survival of bone marrow derived macrophages.

ABSTRACT: We previously showed that survival signaling in TNF?-treated, human THP1-derived macrophages (TDMs) has an obligatory requirement for constitutive Ca(2+) influx through a mechanism involving calmodulin/calmodulin kinase II (CAM/CAMKII). We also demonstrated that such requirement also applies to the protective actions of TNF? in murine bone marrow-derived macrophages (BMDMs) and that TRPC3 channels mediate constitutive Ca(2+) influx. Using a pharmacological approach we here examined if in BMDMs, similarly to TDMs, TNF?-induced survival signaling also involves CAM/CAMKII. In BMDMs, TNF? induced rapid activation of the survival pathways NF?B, AKT and p38MAPK. All these routes were activated in a PI3K-dependent fashion. Activation of AKT and NF?B, but not that of p38MAPK, was abrogated by the CAM inhibitor W7, while KN-62, a CAMKII inhibitor, prevented activation of AKT and p38MAPK but not that of NF?B. Inhibition of CAM or CAMKII completely prevented the protective actions of TNF?. Our observations indicate that in BMDMs CAM and CAMKII have differential contributions to the components of TNF?-dependent survival signaling and underscore a complex interplay among canonical survival routes. These findings set a signaling framework to understand how constitutive Ca(2+) influx couples to macrophage survival in BMDMs.

SUBMITTER: Tano JY

PROVIDER: S-EPMC3485643 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Involvement of calmodulin and calmodulin kinase II in tumor necrosis factor alpha-induced survival of bone marrow derived macrophages.

Tano Jean-Yves JY Lee Robert H RH Vazquez Guillermo G

Biochemical and biophysical research communications 20120916 1

We previously showed that survival signaling in TNFα-treated, human THP1-derived macrophages (TDMs) has an obligatory requirement for constitutive Ca(2+) influx through a mechanism involving calmodulin/calmodulin kinase II (CAM/CAMKII). We also demonstrated that such requirement also applies to the protective actions of TNFα in murine bone marrow-derived macrophages (BMDMs) and that TRPC3 channels mediate constitutive Ca(2+) influx. Using a pharmacological approach we here examined if in BMDMs, ...[more]

PMID: 22989752

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Project description:Published data show that murine bone marrow-derived macrophages (BMDM) restrict growth of avirulent phase II, but not virulent phase I, Coxiella burnetii. Growth restriction of phase II bacteria is thought to result from potentiated recognition of pathogen-associated molecular patterns, which leads to production of inhibitory effector molecules. Past studies have used conditioned medium from L-929 murine fibroblasts as a source of macrophage-colony stimulating factor (M-CSF) to promote differentiation of bone marrow-derived myeloid precursors into macrophages. However, uncharacterized components of conditioned medium, such as variable amounts of type I interferons, can affect macrophage activation status and their permissiveness for infection. In the current study, we show that the C. burnetii Nine Mile phase II (NMII) strain grows robustly in primary macrophages from C57BL/6J mice when bone marrow cells are differentiated with recombinant murine M-CSF (rmM-CSF). Bacteria were readily internalized by BMDM, and replicated within degradative, LAMP1-positive vacuoles to achieve roughly 3 logs of growth over 6 days. Uninfected BMDM did not appreciably express CD38 or Egr2, markers of classically (M1) and alternatively (M2) activated macrophages, respectively, nor did infection change the lack of polarization. In accordance with an M0 phenotype, infected BMDM produced moderate amounts of TNF and nitric oxide. Similar NMII growth results were obtained using C57BL/6J myeloid progenitors immortalized with an estrogen-regulated Hoxb8 (ER-Hoxb8) oncogene. To demonstrate the utility of the ER-Hoxb8 system, myeloid progenitors from natural resistance-associated macrophage protein 1 (Nramp1) C57BL/6J knock-in mice were transduced with ER-Hoxb8, and macrophages were derived from immortalized progenitors using rmM-CSF and infected with NMII. No difference in growth was observed when compared to macrophages from wild type mice, indicating depletion of metal ions by the Nramp1 transporter does not negatively impact NMII growth. Results with NMII were recapitulated in primary macrophages where C57BL/6J Nramp1+ BMDM efficiently killed Salmonella enterica serovar Typhimurium. M-CSF differentiated murine macrophages from bone marrow and conditional ER-Hoxb8 myeloid progenitors will be useful ex vivo models for studying Coxiella-macrophage interactions.

Dataset Information

Involvement of calmodulin and calmodulin kinase II in tumor necrosis factor alpha-induced survival of bone marrow derived macrophages.

Publications

Involvement of calmodulin and calmodulin kinase II in tumor necrosis factor alpha-induced survival of bone marrow derived macrophages.

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