Stable Identifier
Reaction [binding]
Homo sapiens
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The hydrophilic pulmonary surfactant proteins SP-A (SFTPA) and SP-D (SFTPD) belong to the C-type lectin family. Members of the C-type lectin family contain an N-terminal collagen-like domain and a C-terminal carbohydrate recognition domain (CRD) (Kishore U et al. 2006). The CRD allows binding to various components, including carbohydrates, phospholipids or charge patterns found on microbes, allergens and dying cells, while the collagen region can interact with receptor molecules present on immune cells in order to initiate clearance mechanisms (Kishore U et al. 2006). SP-A and SP-D are known to bind to a range of microbial pathogens that invade the lungs (Eggleton P & Reid KB 1999; Crouch E & Wright JR 2001; McCormack FX1 & Whitsett JA 2002; Nayak A et al. 2012; Jakel A et al. 2013). SP-A and SP-D form large oligomeric structures to orchestrate the pulmonary innate immune defense by mechanisms that may involve binding and agglutinating pathogens (Kuan SF et al 1992; Griese M & Starosta V 2005; Yamada C et al. 2006; Kishore U et al. 2006; Zhang L et al. 2001). The direct interaction of SP-A with macrophages was shown to promote phagocytosis of Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa (Van Iwaarden JF et al. 1994; Hickman-Davis JM et al. 2002; Ding J et al. 2004; Mikerov AN et al. 2008; Gil M et al. 2009).

SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR4 domain (sTLR4) and MD2 in a Ca2+ -dependent manner, with involvement of the CRD region (Yamada et al. 2006; Yamazoe M et al. 2008). SP-A was also shown to interact with CD14 (Sano H. et al. 1999). Studies involving gene knock-out mice, murine models of lung hypersensitivity and infection together with functional characterization of cell surface receptors revealed both pro- and anti-inflammatory functions of SP-A and SP-D in the control of lung inflammation in mammals (Guillot L et al. 2002; Madan T et al. 2001, 2005, 2010; Wang JY & Reid KB 2007; Yamada et al. 2006; Yamazoe M et al. 2008; Wang G et al. 2010). Anti-inflammatory effects of SP-A caused inhibition of NF-kB activation and accumulation of inhibitory protein I kappa B-alpha (IkB-alpha) in LPS-challenged alveolar macrophages (AM) (Wu Y et al. 2004). SP-A also inhibited tumor necrosis factor-alpha (TNFalpha) expression induced by smooth LPS but not by rough LPS in the human macrophage-like cell line U937 cells (Sano H. et al. 1999). In addition, SP-A attenuated cell surface binding of smooth LPS and subsequent NF-kB activation in TLR4/MD2 expressing human embryonic kidney (HEK293) cells (Yamada et al. 2006). Like SP-A, SP-D bound to complex of sTLR4:MD2 was found to down regulate a secretion of TNFalpha and activation of NF-kB in LPS-stimulated AM and TLR4/MD-2-transfected HEK293 cells (Yamazoe M et al. 2008). SP-A and SP-D are thought to prevent LPS-elicited inflammatory responses by altering LPS binding to its receptors, TLR4:MD2 or CD14 (Sano H. et al. 1999; Yamada et al. 2006; Yamazoe M et al. 2008).

Literature References
PubMed ID Title Journal Year
16213021 Surfactant proteins SP-A and SP-D: structure, function and receptors

Kishore, U, Madan, T, Shrive, AK, Greenhough, TJ, Waters, P, Chakraborty, T, Reid, KB, Bernal, AL, Ghai, R, Kamran, MF

Mol Immunol 2006
18990700 Pulmonary surfactant protein D inhibits lipopolysaccharide (LPS)-induced inflammatory cell responses by altering LPS binding to its receptors

Mitsuzawa, H, Yamazoe, M, Voelker, DR, Kuroki, Y, Takahashi, H, Ariki, S, Takahashi, M, Sawada, K, Katoh, T, Nishitani, C, Shimizu, T

J. Biol. Chem. 2008
16754682 Surfactant protein A directly interacts with TLR4 and MD-2 and regulates inflammatory cellular response. Importance of supratrimeric oligomerization

Mitsuzawa, H, Himi, T, Sano, H, Yamada, C, Kuroki, Y, Nishitani, C, Shimizu, T

J. Biol. Chem. 2006
16834340 Human pulmonary surfactant protein D binds the extracellular domains of Toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidylinositol and lipopolysaccharide

Mitsuzawa, H, Ohya, M, Yamada, C, Sano, H, Kuroki, Y, Saito, T, Smith, K, Crouch, E, Nishitani, C, Shimizu, T

Biochemistry 2006
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