title: Surfactant protein A modulates the inflammatory response in macrophages during tuberculosis.
abstract: Tuberculosis leads to immune activation and increased human immunodeficiency virus type 1 (HIV-1) replication in the lung. However, in vitro models of mycobacterial infection of human macrophages do not fully reproduce these in vivo observations, suggesting that there are additional host factors. Surfactant protein A (SP-A) is an important mediator of innate immunity in the lung. SP-A levels were assayed in the human lung by using bronchoalveolar lavage (BAL). There was a threefold reduction in SP-A levels during tuberculosis only in the radiographically involved lung segments, and the levels returned to normal after 1 month of treatment. The SP-A levels were inversely correlated with the percentage of neutrophils in BAL fluid, suggesting that low SP-A levels were associated with increased inflammation in the lung. Differentiated THP-1 macrophages were used to test the effect of decreasing SP-A levels on immune function. In the absence of infection with Mycobacterium tuberculosis, SP-A at doses ranging from 5 to 0.01 micro g/ml inhibited both interleukin-6 (IL-6) production and HIV-1 long terminal repeat (LTR) activity. In macrophages infected with M. tuberculosis, SP-A augmented both IL-6 production and HIV-1 LTR activity. To better understand the effect of SP-A, we measured expression of CAAT/enhancer binding protein beta (C/EBPbeta), a transcription factor central to the regulation of IL-6 and the HIV-1 LTR. In macrophages infected with M. tuberculosis, SP-A reduced expression of a dominant negative isoform of C/EBPbeta. These data suggest that SP-A has pleiotropic effects even at the low concentrations found in tuberculosis patients. This protein augments inflammation in the presence of infection and inhibits inflammation in uninfected macrophages, protecting uninvolved lung segments from the deleterious effects of inflammation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, New York University School of Medicine and Bellevue Hospital Chest Service, New York, New York 10016, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Gold
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hoshino
authors.forename: Naohiko
authors.initials: N
authors.lastname: Tanaka
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.forename: Bindu
authors.initials: B
authors.lastname: Raju
authors.forename: Rany
authors.initials: R
authors.lastname: Condos
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weiden
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology; D016325:HIV Long Terminal Repeat; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D037662:Pulmonary Surfactant-Associated Protein A / Q000032:analysis / Q000502:physiology*; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D015850:Interleukin-6; D037662:Pulmonary Surfactant-Associated Protein A