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2?fold decrease (p = 0.006) in tnf mRNA levels 8 hr later ( Figure?5J). To determine if this lipoxin-induced TNF reduction was relevant for infection, we administered LXA4 by caudal vein injection every 12 hr for 4 days starting 1 day after infection. LXA4 treatment resulted in increased bacterial burden ( Figure?5K) and cording frequency ( Figures 5L and 5M). In summary, despite the product of LTA4H being the strongly proinflammatory LTB4, the predominant effect of lta4h deficiency during early mycobacterial infection likely results from increased lipoxins that dampen TNF-mediated protection. Additionally, the greater reduction in LTB4-mediated neutrophil migration in the uninfected zm5961 mutant than in the lta4h morphant in Figure?5H suggested a graduated relationship between LTA4H and TNF levels that would directly modulate susceptibility. To see more test this, we assessed tnf mRNA levels at 1 day post-infection in embryos injected with increasing doses of the lta4h MO. Increasing MO doses correlated inversely with tnf levels in the infected morphants suggesting that LTA4H activity levels Adenylate cyclase may determine the extent of TNF induction at early time points ( Figures S4G and S4H). Our data suggest that zebrafish LTA4H activity orchestrates the balance of pro- and anti-inflammatory eicosanoids so as to affect innate immune resistance to mycobacterial infection. We hypothesized that polymorphisms affecting levels of leukotriene and lipoxin production in humans might influence susceptibility to mycobacterial diseases. Single nucleotide polymorphisms (SNPs) at the human LTA4H locus ( Figures 6A and 6B) define a haplotype associated with significant differences in LTB4 levels following ionomycin stimulation of granulocytes of healthy individuals ( Helgadottir et?al., 2006). We examined whether these LTA4H polymorphisms were associated with susceptibility to TB and to another major mycobacterial disease, leprosy. Vietnamese patients with pulmonary or meningeal TB were compared to Vietnamese controls. All patients and controls were of Kinh ethnicity (Hawn et?al., 2006 and Supplemental Androgen Receptor Antagonist Information). We genotyped six LTA4H SNPs in 692 cases and 759 controls from this cohort ( Table 1). At all six SNPs, genotypes conformed to Hardy Weinberg Equilibrium (HWE) in the control series, but deviated significantly from HWE in the case series. At each site among the cases, fewer heterozygotes were present than expected by HWE expectation, suggesting that heterozygosity at this locus might be protective against TB. Comparison of frequencies of heterozygotes versus homozygotes among TB cases and controls yielded odds ratios (ORs)?