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Published online before print July 6, 2005

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(Journal of Leukocyte Biology. 2005;78:665-674.)
© 2005 by Society for Leukocyte Biology

Negative regulatory role of mannose receptors on human alveolar macrophage proinflammatory cytokine release in vitro

Division of Pulmonary & Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard School of Public Health, and Pediatric Pulmonary Medicine, Massachusetts General Hospital and Harvard Medical School, Boston

¹Correspondence: Division of Pulmonary, Critical Care and Sleep Medicine, Kirstein Hall, Room E/KSB-23, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: hkoziel{at}bidmc.harvard.edu

Alveolar macrophages (AM) are critical components of lung innate immunity and contribute to an effective host response to Pneumocystis pneumonia. Recognition of unopsonized Pneumocystis organisms by human AM is mediated predominantly via mannose receptors and results in phagocytosis, release of reactive oxygen species, and activation of the nuclear transcription factor (NF)-B. However, the AM host defense genes activated by Pneumocystis have not been defined. In the present study, incubation of AM with unopsonized Pneumocystis organisms was not associated with release of interleukin (IL)-1ß, IL-6, or tumor necrosis factor (TNF)- (important cytokines in the host response to Pneumocystis) and did not induce IL-1ß, IL-6, or TNF- mRNA transcripts. These findings were not attributed to Pneumocystis-induced cytopathic changes, as these same AM released IL-8 and matrix metalloproteinase-9 in response to Pneumocystis. NF-B-mediated IL-8 release was independent of Pneumocystis phagocytosis. The observed response was specific, as IL-1ß, IL-6, and TNF- release and mRNA induction were preserved in response to lipopolysaccharide or serum-opsonized Pneumocystis. The absence of IL-1ß, IL-6, and TNF- release in response to Pneumocystis was predominately influenced by AM mannose receptors, as blocking mannose receptors or targeted mannose receptor small interfering RNA functional gene silencing resulted in TNF- release in response to unopsonized Pneumocystis organisms. Furthermore, ligation of AM mannose receptors by unopsonized Pneumocystis organisms reduced Toll-like receptor 4-mediated TNF- release. Taken together, these data suggest that mannose receptors on human AM may suppress select proinflammatory cytokine release and may serve to regulate the innate inflammatory responses to infectious challenge in the lungs.

Key Words: innate immunity • host defense • immunology • phagocytosis

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