期刊
JOURNAL OF IMMUNOLOGY
卷 182, 期 1, 页码 530-537出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.182.1.530
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资金
- National Institutes of Health [HL058897]
- American Lung Association senior research training [RT-78960-N]
- Hartwell Foundation
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [201061/2007-4]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R56HL058897, R01HL058897] Funding Source: NIH RePORTER
Eicosanoid lipid mediators, including prostaglandin E-2 (PGE(2)) and leukotrienes (LTs) B-4 and D-4, are produced in abundance in the infected lung. We have previously demonstrated that individually, PGE(2) suppresses while both classes of LTs augment alveolar macrophage (AM) innate immune functions. In this study, we sought to more appropriately model the milieu at a site of infection by studying the in vitro effects of these lipid mediators on Fc gamma R-mediated phagocytosis when they are present in combination. Consistent with their individual actions, both LTB4 and LTD4 opposed the suppressive effect of PGE(2) on phagocytosis, but only LTB4 did so by mitigating the stimulatory effect of PGE(2) on intracellular cAMP production. Unexpectedly, we observed that IgG-opsonized targets themselves elicited a dose-dependent reduction in intracellular cAMP in AMs, but this was not observed in peritoneal macrophages or elicited peritoneal neutrophils; this effect in AMs was completely abolished by treatment with the LT synthesis inhibitor AA861, the BLT receptor 1 antagonist CP 105,696, and the G alpha i inhibitor pertussis toxin. Of two downstream cAMP effectors, protein kinase A and exchange protein activated by cAMP, the ability of PGE(2) to activate the latter but not the former was abrogated by both LTs B-4 and D-4. Taken together, our results indicate that both classes of LTs oppose the immune suppressive actions of PGE(2), with the stimulatory actions of LTB4 reflecting combinatorial modulation of intracellular cAMP and those of LTD4 being cAMP independent. The Journal of Immunology, 2009, 182: 530-537.
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