Reduced transcript stabilization restricts TNF-α expression in RAW264.7 macrophages infected with pathogenic mycobacteria: evidence for an involvement of lipomannan

Journal of Leukocyte Biology

Helmut Holtmann³  Jens Abel¹  Peter Valentin-Weigand¹  Tina Basler¹  Torsten Eckstein⁴  Wolfgang Bäumer²  Ralph Goethe¹ 

[1] Institut für Mikrobiologie and Institut für Institut für Mikrobiologie and Institut für Institut für Mikrobiologie and Institut fürPharmakologie, Stiftung Tierärztliche Hochschule Hannover, Hannover, Germany; Pharmakologie, Stiftung Tierärztliche Hochschule Hannover, Hannover, Germany; Pharmakologie, Stiftung Tierärztliche Hochschule Hannover, Hannover, Germany;;Institut für Biochemie, Medizinische Hochschule Hannover, Hannover, Germany; and Institut für Biochemie, Medizinische Hochschule Hannover, Hannover, Germany; and Institut für Biochemie, Medizinische Hochschule Hannover, Hannover, Germany; and;Department of Microbiology, Immunology, and Pathology, Colorado State University, Ft. Collins, Colorado, USA Department of Microbiology, Immunology, and Pathology, Colorado State University, Ft. Collins, Colorado, USA Department of Microbiology, Immunology, and Pathology, Colorado State University, Ft. Collins, Colorado, USA

关键词: monocyte;    paratuberculosis;    lipopolysaccharide;    lipoglycan;    p38 mitogen-activated protein kinase;    post-transcriptional gene regulation;   

DOI  :  10.1189/jlb.0309207

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Despite the critical role that TNF-α 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-α gene expression was substantially lower than in macrophages infected with nonpathogenic MS or stimulated with LPS. TNF-α transcription alone could not fully explain the differential TNF-α mRNA expression, suggesting that there must be a substantial contribution by post-transcriptional mechanisms. Accordingly, we found reduced TNF-α mRNA stability in MAP-infected macrophages. Further comparison of MAP- and MS-infected macrophages revealed that lower TNF-α 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-α 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-α mRNA stabilization as a result of their structural cell-wall components such as LM and thereby, restrict TNF-α expression in macrophages.

【 授权许可】

Unknown