Role of 5-lipoxygenase in IL-13-induced pulmonary inflammation and remodeling.
Exaggerated levels of IL-13 and leukotriene (LT) pathway activation frequently coexist at sites of Th2 inflammation and in tissue fibrotic responses. However, the relationship(s) between the IL-13 and LTs in these responses have not been defined. We hypothesized that the 5-lipoxygenase (5-LO) pathway of LT metabolism plays an important role in the pathogenesis of IL-13-induced chronic inflammation and remodeling. To test this hypothesis, we evaluated the effects of IL-13 on components of the 5-LO metabolic and activation pathways. We also compared the effects of transgenic IL-13 in C57BL/6 mice with wild-type and null 5-LO genetic loci. These studies demonstrate that IL-13 increases the levels of mRNA encoding cytosolic phospholipase A(2), LTA(4) hydrolase, and 5-LO-activating protein without altering the expression of 5-LO, LTC(4) synthase, LTB(4) receptors 1 and 2, and cysteinyl-LT receptors 1 and 2. They also demonstrate that this activation is associated with the enhanced accumulation of LTB(4) but not of cysteinyl-LTs. Furthermore, they demonstrate that this stimulation plays a critical role in the pathogenesis of IL-13-induced inflammation, tissue fibrosis, and respiratory failure-induced death while inhibiting alveolar remodeling. Lastly, mechanistic insights are provided by demonstrating that IL-13-induced 5-LO activation is required for optimal stimulation and activation of TGF-beta(1) and the inhibition of matrix metalloproteinase-12. When viewed in combination, these studies demonstrate that 5-LO plays an important role in IL-13-induced inflammation and remodeling.
Shim
Yun M
YM
Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Zhu
Zhou
Z
Zheng
Tao
T
Lee
Chun G
CG
Homer
Robert J
RJ
Ma
Bing
B
Elias
Jack A
JA
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002908:Chronic Disease; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015289:Leukotrienes / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000276:immunology / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D018793:Interleukin-13; D015289:Leukotrienes; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001094:Arachidonate 5-Lipoxygenase; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12; D015232:Dinoprostone