title: An enzyme that inactivates the inflammatory mediator leukotriene b4 restricts mycobacterial infection.
abstract: While tuberculosis susceptibility has historically been ascribed to failed inflammation, it is now known that an excess of leukotriene A4 hydrolase (LTA4H), which catalyzes the final step in leukotriene B4 (LTB4) synthesis, produces a hyperinflammatory state and tuberculosis susceptibility. Here we show that the LTB4-inactivating enzyme leukotriene B4 dehydrogenase/prostaglandin reductase 1 (LTB4DH/PTGR1) restricts inflammation and independently confers resistance to tuberculous infection. LTB4DH overexpression counters the susceptibility resulting from LTA4H excess while ltb4dh-deficient animals can be rescued pharmacologically by LTB4 receptor antagonists. These data place LTB4DH as a key modulator of TB susceptibility and suggest new tuberculosis therapeutic strategies.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America. david.tobin@duke.edu
authors.forename: David M
authors.initials: DM
authors.lastname: Tobin
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Roca
authors.forename: John P
authors.initials: JP
authors.lastname: Ray
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Ko
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism*; D008969:Molecular Sequence Data; D009164:Mycobacterium Infections / Q000201:enzymology* / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000378:metabolism; D016415:Sequence Alignment; D014376:Tuberculosis / Q000201:enzymology* / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D000429:Alcohol Oxidoreductases; C082646:leukotriene B4 12-hydroxydehydrogenase