Reactome | SFTPA/SFTPD binds TLR2:TLR1

SFTPA/SFTPD binds TLR2:TLR1

Stable Identifier

R-HSA-5432814

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

ReviewStatus

5/5

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The lung surfactant proteins SP-A (also known as SFTPA) and SP-D (SFTPD) have been implicated in the regulation of pulmonary host defense and inflammation. SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR2 domain (TLR2) via its C-terminal carbohydrate recognition domain (CRD) in a Ca(2+)-dependent manner (Murakami S et al. 2002; Ohya M et al. 2006). SP-A downregulated TLR2-mediated signaling and tumor necrosis factor alpha (TNFalpha) secretion in TLR2-transfected human embryonic kidney 293 (HEK293) cells upon stimulation with TLR2 ligands such as fungal cell surface component zymosan or bacterial peptidoglycan (PGN) (Murakami S et al. 2002; Sato M et al. 2003). Similarly, SP-A significantly reduced PGN-elicited TNFalpha secretion by human leukemic monocyte lymphoma U937 cell line and rat alveolar macrophages (Murakami S et al. 2002). In primary human monocyte-derived macrophage SP-A regulated TLR2 and TLR4 activity by diminishing proinflammatory cytokine production as the result of a decreased phosphorylation of a key regulator of NFkB, IkBalpha. Nuclear translocation of NFkB-p65 (RELA) was also inhibited (Henning LN et al. 2008). SP-A downregulated kinases upstream of IkBalpha by decreasing the phosphorylation of Akt and MAPKs in response to either LPS (TLR4 ligand) or Pam3Cys (TLR2 ligand) (Henning LN et al. 2008). In addition, SP-A upregulated surface protein expression of TLR2 on macrophages, while it did not affect TLR4 surface expression. The increased TLR2 expression is thought to enhance pathogen recognition by TLR2, while SP-A mediated inhibition of TLR signaling may protect from an overreactive inflammatory response (Henning LN et al. 2008).

Literature References

PubMed ID	Title	Journal	Year
12817025	Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A Konishi, M, Sano, H, Kuroki, Y, Asai, Y, Imaizumi, H, Takahashi, T, Takahashi, H, Sato, M, Kudo, K, Iwaki, D	J. Immunol.	2003
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
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
11724772	Surfactant protein A inhibits peptidoglycan-induced tumor necrosis factor-alpha secretion in U937 cells and alveolar macrophages by direct interaction with toll-like receptor 2 Mitsuzawa, H, Sano, H, Voelker, DR, Kuroki, Y, Takahashi, H, Akino, T, Murakami, S, Iwaki, D	J. Biol. Chem.	2002