Macrophage’s Proinflammatory Response to a Mycobacterial Infection Is Dependent on Sphingosine Kinase-Mediated Activation of Phosphatidylinositol Phospholipase C, Protein Kinase C, ERK1/2, and Phosphatidylinositol 3-Kinase
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Previous studies have shown that the ability of Mycobacterium tuberculosis to block a Ca2+ flux is an important step in its capacity to halt phagosome maturation. This affect on Ca2+ release results from M. tuberculosis inhibition of sphingosine kinase (SPK) activity. However, these studies did not address the potential role of SPK and Ca2+ in other aspects of macrophage activation including production of proinflammatory mediators. We previously showed that nonpathogenic Mycobacterium smegmatis and to a lesser extent pathogenic Mycobacterium avium, activate Ca2+-dependent calmodulin/calmodulin kinase and MAPK pathways in murine macrophages leading to TNF-α production. However, whether SPK functions in promoting MAPK activation upon mycobacterial infection was not defined in these studies. In the present work we found that SPK is required for ERK1/2 activation in murine macrophages infected with either M. avium or M. smegmatis. Phosphoinositide-specific phospholipase C (PI-PLC) and conventional protein kinase C (cPKC) were also important for ERK1/2 activation. Moreover, there was increased activation of cPKC and PI3K in macrophages infected with M. smegmatis compared with M. avium. This cPKC and PI3K activation was dependent on SPK and PI-PLC. Finally, in macrophages infected with M. smegmatis compared with M. avium, we observed enhanced secretion of TNF-α, IL-6, RANTES, and G-CSF and found production of these inflammatory mediators to be dependent on SPK, PI-PLC, cPKC, and PI3K. These studies are the first to show that the macrophage proinflammatory response following a mycobacterial infection is regulated by SPK/PI-PLC/PKC activation of ERK1/2 and PI3K pathways.
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PKC isozymes are involved in the pro-inflammatory response mediated by macrophages and microglia through activation of the NF-κB inflammation pathway.
“PKC isozymes are involved in the pro-inflammatory response mediated by macrophages [103] and, more recently, microglia [104] through activation of the NF-κB inflammation pathway.”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [103]
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- Authors
- Yadav, M., Clark, L., & Schorey, J. S.
- Affiliations
- University of Notre Dame (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-05-01
- Volume
- 176
- Issue
- 9
- Pages
- 5494-5503
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2145959508
- Cited by
- 64
- References
- 63
- Citations by year
- 2024: 1 · 2023: 3 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 6 · 2012: 5
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI056979, AI056979, AI052439, R01AI052439)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Keywords
- sphingosine kinase, Mycobacterium tuberculosis, Mycobacterium smegmatis, Mycobacterium avium, macrophage activation, inflammatory cytokines, ERK1/2 activation, phosphatidylinositol-specific phospholipase C, protein kinase C, phosphatidylinositol 3-kinase, MAPK signaling, calcium signaling, calcium/calmodulin-dependent protein kinase, TNF-α, interleukin-6, RANTES, granulocyte colony-stimulating factor, phagosome maturation
- MeSH terms
- Sphingosine Kinase, Animals, Bone Marrow, Calcium, Cells, Cultured, Enzyme Activation, Macrophages, Mycobacterium avium, Mycobacterium Infections, Protein Kinase C, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Granulocyte Colony-Stimulating Factor, Phosphotransferases (Alcohol Group Acceptor), Inflammation Mediators, Chemokine CCL5, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase 1, Mycobacterium smegmatis, Phosphatidylinositol Diacylglycerol-Lyase, Extracellular Signal-Regulated MAP Kinases, Mitogen-Activated Protein Kinase 3, Mice, Phosphoinositide Phospholipase C
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