MAP infection depresses TNF-alpha output in macrophages
Kofi
Reduced transcript stabilization restricts TNF-{alpha} expression in
RAW264.7 macrophages infected with pathogenic mycobacteria: evidence for
an involvement of lipomannan.
Basler T, Holtmann H, Abel J, Eckstein T, Baumer W, Valentin-Weigand P,
Goethe R.
Institut fur *Mikrobiologie and Institut furPharmakologie, Stiftung
Tierarztliche Hochschule Hannover, Hannover, Germany;Institut fur
Biochemie, Medizinische Hochschule Hannover, Hannover, Germany;
andDepartment of Microbiology, Immunology, and Pathology, Colorado State
University, Ft. Collins, Colorado, USA.
Despite the critical role that TNF-alpha plays in the containment of
mycobacterial infection, the mechanisms involved in regulation of its
expression by mycobacteria are poorly defined. We addressed this
question by studying MAP, which causes a chronic enteritis in ruminants
and is linked to human Crohn's disease. We found that in MAP-infected
macrophages, TNF-alpha gene expression was substantially lower than in
macrophages infected with nonpathogenic MS or stimulated with LPS.
TNF-alpha transcription alone could not fully explain the differential
TNF-alpha mRNA expression, suggesting that there must be a substantial
contribution by post-transcriptional mechanisms. Accordingly, we found
reduced TNF-alpha mRNA stability in MAP-infected macrophages. Further
comparison of MAP- and MS-infected macrophages revealed that lower
TNF-alpha mRNA stability combined with lower mRNA and protein expression
in MAP-infected macrophages correlated with lower p38 MAPK
phosphorylation. Theses findings were independent of viability of MAP
and MS. We demonstrate that the major mycobacterial cell-wall lipoglycan
LM of MAP and MS induced TNF-alpha mRNA transcription, but only the
MS-LM induced p38 MAPK-dependent transcript stabilization. Overall, our
data suggest that pathogenic mycobacteria cause weak p38 MAPK activation
and TNF-alpha mRNA stabilization as a result of their structural
cell-wall components such as LM and thereby, restrict TNF-alpha
expression in macrophages.
PMID: 19850884