title: Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production.
abstract: Th1 type cytokine responses are critical in the control of Mycobacterium tuberculosis infection. Recent findings indicate that 5-lipoxygenase-dependent (5-LO-dependent) lipoxins regulate host IL-12 production in vivo. Here, we establish lipoxins as key chemical mediators in resistance to M. tuberculosis infection. High levels of lipoxin A4 (LXA4) were detected in sera from infected WT but not infected 5-LO-deficient mice. Moreover, lungs from M. tuberculosis-infected 5-lo-/- animals showed increased IL-12, IFN-gamma, and NO synthase 2 (NOS2) mRNA levels compared with the same tissues in WT mice. Similarly, splenocyte recall responses were enhanced in mycobacteria-infected 5-lo-/- versus WT mice. Importantly, bacterial burdens in 5-lo-/- lungs were significantly lower than those from WT mice, and this enhancement in the resistance of the 5-lo-/- animals to M. tuberculosis was completely prevented by administration of a stable LXA4 analog. Together our results demonstrate that lipoxins negatively regulate protective Th1 responses against mycobacterial infection in vivo and suggest that the inhibition of lipoxin biosynthesis could serve as a strategy for enhancing host resistance to M. tuberculosis.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Bafica
authors.forename: Charles A
authors.initials: CA
authors.lastname: Scanga
authors.forename: Charles
authors.initials: C
authors.lastname: Serhan
authors.forename: Fabiana
authors.initials: F
authors.lastname: Machado
authors.forename: Sandy
authors.initials: S
authors.lastname: White
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.forename: Julio
authors.initials: J
authors.lastname: Aliberti
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D044045:Lipoxins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines; D044045:Lipoxins; C040527:lipoxin A4; D001094:Arachidonate 5-Lipoxygenase; D019001:Nitric Oxide Synthase