Surfactant protein D (SP-D) plays important roles in the regulation of innate immune responses in the lung. We have previously shown that SP-D can agglutinate and enhance the macrophage-dependent killing of specific unencapsulated phase variants of Klebsiella pneumoniae. In the present studies, we used 16 clinical isolates of Klebsiella representing four O-serotypes and examined the interaction of SP-D with their isolated LPSs. Although SP-D bound to the core oligosaccharide of rough LPS from all isolates, it selectively bound to smooth forms of LPS expressed by O-serotypes with mannose-rich repeating units in their O-polysaccharides. SP-D was more potent in agglutinating unencapsulated phase variants of O-serotypes expressing these SP-D “reactive” O-polysaccharides, and more effectively inhibited the adhesion of these serotypes to lung epithelial cells. This novel anti-adhesion activity required the multimerization of trimeric SP-D subunits (dodecamers). Klebsiella serotypes expressing “nonreactive” LPS O-Ags were isolated at a significantly higher frequency from patients with K. pneumoniae. Our findings suggest that SP-D plays important roles in the clearance of opportunistic Gram-negative bacteria and contributes to known serotypic differences in the pathogenicity of Klebsiella through specific interactions with O-polysaccharides.
Pulmonary surfactant protein D (SP-D)1 is a member of the collectin (collagenous lectin) subfamily of mammalian C-type lectins, which includes pulmonary surfactant protein A (SP-A), serum mannose-binding lectin, and at least two bovine serum lectins related to SP-D, conglutinin and CL-43 (1, 2). The genes for both lung collectins and mannose-binding lectin are encoded in close proximity on human chromosome 10q. The pulmonary collectins, like the homologous serum proteins, are believed to contribute to innate (nonclonal) immunity and the host response to microorganisms (2). In addition, both SP-A and SP-D may contribute to the regulation of surfactant lipid homeostasis under certain circumstances in vivo (3-5).SP-A and SP-D are secreted into the distal airways and pulmonary alveoli by Clara cells and type II pneumocytes. The expression of SP-A and SP-D by these cells is increased following many forms of pulmonary injury (2), and the rapid increase in SP-A and SP-D accumulation following intratracheal instillation of bacterial endotoxin suggests that they contribute to a pulmonary acute phase response (6). However, the regulation of these responses is not understood. We have previously shown that DNA sequences within 285 bp of the start site of transcription of the human SP-D promoter are able to confer glucocorticoid-responsive gene expression in H441 human lung adenocarcinoma cells but not liver HepG2 cells (7), suggesting that the proximal sequence contains information sufficient to direct lung-restricted expression. Sequence analysis of the proximal promoter suggested potential regulatory roles for a variety of ubiquitous and lung-restricted transcription factors.In considering the potential contributions of these regulatory motifs to SP-D gene regulation, we initially focused our attention on the AP-1 consensus (5Ј-TGAGTCA-3Ј) at Ϫ109 bp relative to the start site of transcription (7). Preliminary footprinting assays showed preferential protection of this motif and its contiguous flanking sequences by nuclear extracts from H441 cells. In addition, an identical AP-1 motif is spatially conserved in the rat and mouse promoters (7,8) and in the promoter of the homologous bovine conglutinin gene (9, 10) (Fig. 1). Because alterations in the composition of the AP-1 complex regulate a wide variety of transcriptional events associated with cellular differentiation and the response to environmental stimuli including cell injury, inflammation, and the systemic acute phase response, we hypothesized that the AP-1 motif plays important roles in the regulation of SP-D expression.The flanking regions of the conserved AP-1 motif also contain sequences resembling binding sites for factors known to regulate respiratory epithelial cell differentiation and the expression of various secreted lung proteins including Clara cellspecific protein (CCSP) and SP-A, -B, and -C (11). These include potential binding sites for the homeodomain-containing protein, thyroid transcription factor 1 (TTF-1), and the forkhead/winged helix transcript...
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