臨床検査52巻8号

2008年08月発行

今月の主題 自然免疫と生体防御レクチン 総説

肺サーファクタント蛋白質(SP-A，SP-D)の免疫調節機能

著者： 黒木由夫¹ 山添雅己¹ 澤田格¹ 有木茂¹

所属機関： ¹札幌医科大学医学部医化学講座

ページ範囲：P.851 - P.859

　肺サーファクタントは，肺胞Ⅱ型細胞で合成され，肺胞腔に分泌される脂質蛋白質複合体で，その物理化学的表面活性作用により肺胞虚脱を防ぐことにより安定な呼吸を維持する生理活性物質である．肺は常に外界に開放しているので，肺サーファクタントによる生体防御機能は重要である．肺サーファクタント蛋白質のSP-AとSP-DはC型レクチンのコレクチンに属しており，レクチンドメインとコラーゲン様ドメインを有するハイブリッド分子で，肺における自然免疫機能を担っている．in vivoおよびin vitroの研究により，肺コレクチンによる免疫調節機能の分子機構が明らかになってきた．

参考文献

1) Kuroki Y, Voelker DR：Pulmonary surfactant proteins. J Biol Chem　269：25943-25946, 1994

2) Nogee LM, de Mello DE, Dehner LP, et al：Brief report：deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Eng J Med　328：406-410, 1993

3) Nogee LM, Dunbar AE 3rd, Wert SE, et al：A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med　344：573-579, 2001

4) Kuroki Y, Takahashi M, Nishitani C：Pulmonary collectins in innate immunity of the lung. Cell Microbiol　9：1871-1879, 2007

adult. Cell　86：973-983, 1996

6) Medzhitov R, Preston-Hurlburt P, Janeway CA Jr.：A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature　388：394-397, 1997

7) Akira S, Takeda K：Toll-like receptor signalling. Nat Rev Immunol　4：499-511, 2004

8) Mitsuzawa H, Nishitani C, Hyakushima N, et al：Recombinant soluble forms of extracellular TLR4 domain and MD-2 inhibit lipopolysaccharide binding on cell surface and dampen lipopolysaccharide-induced pulmonary inflammation in mice. J Immunol　177：8133-8139, 2006

9) Iwaki D, Mitsuzawa H, Murakami S, et al：The extracellular toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus. J Biol Chem　277：24315-24320, 2002

10) Mitsuzawa H, Wada I, Sano H, et al：Extracellular Toll-like receptor 2 region containing Ser40-Ile64 but not Cys30-Ser39 is critical for the recognition of Staphylococcus aureus peptidoglycan. J Biol Chem　276：41350-41356, 2001

11) Sato M, Sano H, Iwaki D, et al：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. J Immunol　171：417-425, 2003

12) Borron P, McIntosh JC, Korfhagen TR, et al：Surfactant-associated protein A inhibits LPS-induced cytokine and nitric oxide production in vivo. Am J Physiol Lung Cell Mol Physiol　278：L840-L847, 2000

13) LeVine AM, Whitsett JA, Gwozdz JA, et al：Distinct effects of surfactant protein A or D deficiency during bacterial infection on the lung. J Immunol　165：3934-3940, 2000

14) Korfhagen TR, Sheftelyevich V, Burhans MS, et al：Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo. J Biol Chem　273：28438-28443, 1998

15) Wert SE, Yoshida M, LeVine AM, et al：Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc Natl Acad Sci USA　97：5972-5977, 2000

16) Yoshida M, Korfhagen TR, Whitsett JA：Surfactant protein D regulates NF-kappa B and matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways. J Immunol　166：7514-7519, 2001

17) Betsuyaku T, Kuroki Y, Nagai K, et al：Effects of ageing and smoking on SP-A and SP-D levels in bronchoalveolar lavage fluid. Eur Respir J　964：964-970, 2004

18) Sano H, Sohma H, Muta T, et al：Pulmonary surfactant protein A modulates the cellular response to smooth and rough lipopolysaccharides by interaction with CD14. J Immunol　163：387-395, 1999

19) Murakami S, Iwaki D, Mitsuzawa H, et al：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. J Biol Chem　277：6830-6837, 2002

20) Yamada C, Sano H, Shimizu T, et al：Surfactant protein A directly interacts with TLR4 and MD-2 and regulates inflammatory cellular response. Importance of supratrimeric oligomerization. J Biol Chem　281：21771-21780, 2006

21) Ohya M, Nishitani C, Sano H, et al：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. Biochemistry　45：8657-8664, 2006

22) Gardai SJ, Xiao YQ, Dickinson M, et al：By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell　115：13-23, 2003

23) Kudo K, Sano H, Takahashi H, et al：Pulmonary collectins enhance phagocytosis of Mycobacterium avium through increased activity of mannose receptor. J Immunol　172：7592-7602, 2004

24) Geertsma MF, Nibbering PH, Haagsman HP, et al：Binding of surfactant protein A to C1q receptors mediates phagocytosis of Staphylococcus aureus by monocytes. Am J Physiol　267：L578-L584, 1994

25) Weikert LF, Edwards K, Chroneos ZC, et al：SP-A enhances uptake of bacillus Calmette-Guérin by macrophages through a specific SP-A receptor. Am J Physiol　272：L989-L995, 1997

26) Tenner AJ, Robinson SL, Borchelt J, et al：Human pulmonary surfactant protein(SP-A), a protein structurally homologous to C1q, can enhance FcR-and CR1-mediated phagocytosis. J Biol Chem　264：13923-13928, 1989

27) Beharka AA, Gaynor CD, Kang BK, et al：Pulmonary surfactant protein A up-regulates activity of the mannose receptor, a pattern recognition receptor expressed on human macrophages. J Immunol　169：3565-3673, 2002

28) Ferguson JS, Voelker DR, McCormack FX, et al：Surfactant protein D binds to Mycobacterium tuberculosis bacilli and lipoarabinomannan via carbohydrate-lectin interactions resulting in reduced phagocytosis of the bacteria by macrophages. J Immunol　163：312-321, 1999

29) Kuronuma K, Sano H, Kato K, et al：Pulmonary surfactant protein A augments the phagocytosis of Streptococcus pneumoniae by alveolar macrophages through a casein kinase 2-dependent increase of cell surface localization of scavenger receptor A. J Biol Chem　279：21421-21430, 2004

30) Sano H, Ishino M, Krämer H, et al：The microtubule-binding protein Hook3 interacts with a cytoplasmic domain of scavenger receptor A. J Biol Chem　282：7973-7981, 2007