Differential Activation of the Transcription Factor Cyclic AMP Response Element Binding Protein (CREB) in Macrophages following Infection with Pathogenic and Nonpathogenic Mycobacteria and Role for CREB in Tumor Necrosis Factor Alpha Production
Open Access
- 1 January 2005
- journal article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 73 (1), 514-522
- https://doi.org/10.1128/iai.73.1.514-522.2005
Abstract
Previous studies in our laboratory have shown a differential activation of the mitogen-activated protein kinases (MAPKs) in primary bone marrow-derived macrophages following infection with pathogenic Mycobacterium avium compared to the activation following infection with nonpathogenic Mycobacterium smegmatis . Additionally, M. smegmatis -infected macrophages produced significantly elevated levels of tumor necrosis factor alpha (TNF-α) compared to the levels produced by M. avium -infected macrophages. The TNF-α production was dependent on both p38 and extracellular signal-regulated kinase 1/2 (ERK 1/2) activation. However, the macrophage transcription factors downstream of the MAPKs, which were required for TNF-α production, remained undefined. In this study we determined that the transcription factor cyclic AMP response element binding protein (CREB) is significantly more activated in M. smegmatis -infected macrophages than in M. avium -infected macrophages. We also found that CREB activation was dependent on p38 and protein kinase A but not on ERK 1/2 or calmodulin kinase II. Moreover, mutating the cAMP-responsive element on the TNF-α promoter resulted in significantly diminished promoter activity following M. smegmatis infection but not M. avium infection. The inability of macrophages infected with M. avium to sustain MAPK activation and to produce high levels of TNF-α was due, in part, to an increase in serine/threonine phosphatase PP2A activity. Our studies are the first to demonstrate an important role for the transcription factor CREB in TNF-α production by mycobacterium-infected macrophages, as well as a role for M. avium 's induction of PP2A phosphatase activity as a mechanism to limit macrophage activation.Keywords
This publication has 35 references indexed in Scilit:
- Modulation of Endotoxin-Induced Endothelial Function by Calcium/Calmodulin-Dependent Protein KinaseShock, 2003
- Differential Regulation of the Mitogen-Activated Protein Kinases by Pathogenic and Nonpathogenic MycobacteriaInfection and Immunity, 2002
- Reinventing the Wheel of Cyclic AMPAnnals of the New York Academy of Sciences, 2002
- Transcriptional regulation by the phosphorylation-dependent factor CREBNature Reviews Molecular Cell Biology, 2001
- Cytokine Profiles in Immunocompetent Persons Infected withMycobacterium aviumComplexThe Journal of Infectious Diseases, 2001
- Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB KinaseScience, 1996
- Differential release of tumor necrosis factor-α from murine peritoneal macrophages stimulated with virulent and avirulent species of mycobacteriaFEMS Immunology & Medical Microbiology, 1994
- Lack of Acidification in Mycobacterium Phagosomes Produced by Exclusion of the Vesicular Proton-ATPaseScience, 1994
- Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133Cell, 1989
- An improved procedure for identifying and quantitating protein phosphatases in mammalian tissuesFEBS Letters, 1989