title: TNF influences chemokine expression of macrophages in vitro and that of CD11b+ cells in vivo during Mycobacterium tuberculosis infection.
abstract: Granulomas, focal accumulations of immune cells, form in the lung during Mycobacterium tuberculosis infection. Chemokines, chemotactic cytokines, are logical candidates for inducing migration of T lymphocytes and monocytes to and within the lung. TNF influences chemokine expression in some models. TNF-deficient mice infected with M. tuberculosis are highly susceptible to disease, and granuloma formation is inhibited. Through in vitro assays, we demonstrate that neutralization of TNF in M. tuberculosis-infected macrophages led to a reduction in many inflammatory chemokines, such as C-C chemokine ligand 5, CXC ligand 9 (CXCL9), and CXCL10. In TNF-deficient mice, immune cells migrated to the lungs early after infection, but did not organize to form granulomas within the lung. Although chemokine expression, as measured in whole lung tissue, was not different, the expression of chemokines in the CD11b(+) subset of cells isolated ex vivo from the lungs of TNF-deficient mice had reduced expression of C-C chemokine ligand 5, CXCL9, and CXCL10 at early time points after TNF neutralization. Local expression of CXCR3-binding chemokines within the lungs, as determined by in situ hybridization, was also affected by TNF. Therefore, TNF affects the expression of chemokines by macrophages in vitro and CD11b(+) cells in vivo, which probably influences the local chemokine gradients and granuloma formation.
authors.affiliation: Department of Molecular Genetics and Biochemistry and Molecular Virology and Microbiology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Holly M Scott
authors.initials: HM
authors.lastname: Algood
authors.forename: Philana Ling
authors.initials: PL
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Yankura
authors.forename: Alvin
authors.initials: A
authors.lastname: Jones
authors.forename: John
authors.initials: J
authors.lastname: Chan
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000032:analysis*; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines / Q000096:biosynthesis*; D019743:Chemokines, CXC / Q000096:biosynthesis; D004198:Disease Susceptibility; D005260:Female; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D039481:CD11b Antigen; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha