凝血酶調節素是一個具有抗凝血功能的穿膜蛋白，在內皮細胞、角質細胞、嗜中性白血球、單核球細胞以及巨噬細胞都有表現。過去的研究指出凝血酶調節素不只具有抗凝血作用，也參與其它生理調控，例如細胞間的黏附、發炎反應、血管新生以及腫瘤生長的過程。巨噬細胞主要可以活化成兩種型態，典型活化的巨噬細胞(或稱M1巨噬細胞)與另類活化的巨噬細胞(或稱M2巨噬細胞)。M1巨噬細胞會表現較高的發炎細胞激素，而M2巨噬細胞則高度表現巨噬細胞甘露醣受體與介質白素-10。巨噬細胞能夠浸潤至腫瘤中並且分泌血管新生因子促進腫瘤生長。過去的文獻指出單核球細胞及巨噬細胞能表現凝血酶調節素，然而對於單核球細胞中的凝血酶調節素的功能仍不清楚。在此次的研究中，我們利用特定在髓細胞剔除凝血酶調節素的小鼠來研究在單核球細胞中的凝血酶調節素在腫瘤生長時所扮演的角色。研究結果顯示黑色素瘤的腫瘤體積及腫瘤重量在髓細胞剔除凝血酶調節素的小鼠中有增加的趨勢，並且巨噬細胞浸潤至黑色素瘤的數量也增加；而缺乏凝血酶調節素的巨噬細胞具有較高的巨噬細胞群落刺激因子受體及CC趨化因子受體2的表現，能夠引起與巨噬細胞爬行相關的訊息傳遞途徑活化，包括細胞外訊號調節激酶1/2、Akt2、Cdc42。此外，缺乏凝血酶調節素的巨噬細胞能高度表現巨噬細胞甘露醣受體與介質白素-10，顯示缺乏凝血酶調節素的巨噬細胞具有M2巨噬細胞的特徵。綜合以上結果，我們證明凝血酶調節素能調控巨噬細胞的化學趨性能力，進而增加巨噬細胞浸潤至黑色素瘤的數量，促進黑色素瘤的生長。

Thrombomodulin (TM), a well-characterized anticoagulant protein, is expressed in many cell types, including endothelial cells, keratinocytes, neutrophils, monocytes, and macrophages. Recent studies have reported that TM not only regulates haemostasis but also is involved in other biological processes such as cell-cell adhesion, inflammation, angiogenesis, and tumor progression. Increasing evidence indicates that macrophages can be polarized into two main phenotypes: classically activated macrophages (or M1 macrophages) and alternatively activated macrophages (or M2 macrophages). M1 macrophages favor to express inflammatory cytokines, and M2 macrophages highly express macrophage mannose receptor (MMR) and interleukin (IL)-10. It has been demonstrated that macrophages can infiltrate into tumors and promote tumor growth by secreting angiogenic factors. Although TM expression has been found, the function of monocytic TM is still poorly understood. In this study, we used the myeloid-specific TM-deficient mice (LysMcre/TMflox/flox mice) to investigate the role of monocytic TM in tumor growth. The results showed that melanoma tumor volume and tumor weight were increased in LysMcre/TMflox/flox mice, and the number of infiltrated macrophages in the tumor of LysMcre/TMflox/flox mice was also increased. In addition, the elevation of migration-related signaling pathways in TM-deficient macrophages, including extracellular signal-regulated kinase (ERK) 1/2, Akt2, and Cdc42, was caused by the up-regulated expression of macrophage colony-stimulating factor receptor (MCSFR) and CC chemokine receptor 2 (CCR2). Furthermore, the expression of MMR and IL-10 was also enhanced in TM-deficient macrophages, indicating that TM-deficient macrophages may display M2-like phenotype. In conclusion, we demonstrate that TM regulates macrophage chemotaxis and loss of monocytic TM in mice promotes melanoma tumor growth by the increase in macrophage infiltration.

1. Weiler, H., and Isermann, B. H. (2003) Thrombomodulin. J Thromb Haemost 1, 1515-1524
2. Sadler, J. E. (1997) Thrombomodulin structure and function. Thromb Haemost 78, 392-395
3. Owen, W. G., and Esmon, C. T. (1981) Functional properties of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 256, 5532-5535
4. Esmon, C. T., and Owen, W. G. (1981) Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci U S A 78, 2249-2252
5. Esmon, C. T. (2003) The protein C pathway. Chest 124, 26S-32S
6. Esmon, C. T., Esmon, N. L., and Harris, K. W. (1982) Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem 257, 7944-7947
7. Suzuki, K., Kusumoto, H., Deyashiki, Y., Nishioka, J., Maruyama, I., Zushi, M., Kawahara, S., Honda, G., Yamamoto, S., and Horiguchi, S. (1987) Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J 6, 1891-1897
8. Fuentes-Prior, P., Iwanaga, Y., Huber, R., Pagila, R., Rumennik, G., Seto, M., Morser, J., Light, D. R., and Bode, W. (2000) Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature 404, 518-525
9. Bernard, G. R., Vincent, J. L., Laterre, P. F., LaRosa, S. P., Dhainaut, J. F., Lopez-Rodriguez, A., Steingrub, J. S., Garber, G. E., Helterbrand, J. D., Ely, E. W., and Fisher, C. J., Jr. (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344, 699-709
10. McCachren, S. S., Diggs, J., Weinberg, J. B., and Dittman, W. A. (1991) Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages. Blood 78, 3128-3132
11. Conway, E. M., Nowakowski, B., and Steiner-Mosonyi, M. (1992) Human neutrophils synthesize thrombomodulin that does not promote thrombin-dependent protein C activation. Blood 80, 1254-1263
12. Lager, D. J., Callaghan, E. J., Worth, S. F., Raife, T. J., and Lentz, S. R. (1995) Cellular localization of thrombomodulin in human epithelium and squamous malignancies. Am J Pathol 146, 933-943
13. Bretschneider, E., Uzonyi, B., Weber, A. A., Fischer, J. W., Pape, R., Lotzer, K., and Schror, K. (2007) Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res 100, 255-262
14. Mizutani, H., Hayashi, T., Nouchi, N., Ohyanagi, S., Hashimoto, K., Shimizu, M., and Suzuki, K. (1994) Functional and immunoreactive thrombomodulin expressed by keratinocytes. J Invest Dermatol 103, 825-828
15. Healy, A. M., Rayburn, H. B., Rosenberg, R. D., and Weiler, H. (1995) Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci U S A 92, 850-854
16. Huang, H. C., Shi, G. Y., Jiang, S. J., Shi, C. S., Wu, C. M., Yang, H. Y., and Wu, H. L. (2003) Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. J Biol Chem 278, 46750-46759
17. Conway, E. M., Van de Wouwer, M., Pollefeyt, S., Jurk, K., Van Aken, H., De Vriese, A., Weitz, J. I., Weiler, H., Hellings, P. W., Schaeffer, P., Herbert, J. M., Collen, D., and Theilmeier, G. (2002) The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med 196, 565-577
18. Shi, C. S., Shi, G. Y., Hsiao, S. M., Kao, Y. C., Kuo, K. L., Ma, C. Y., Kuo, C. H., Chang, B. I., Chang, C. F., Lin, C. H., Wong, C. H., and Wu, H. L. (2008) Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response. Blood 112, 3661-3670
19. Kao, Y. C., Wu, L. W., Shi, C. S., Chu, C. H., Huang, C. W., Kuo, C. P., Sheu, H. M., Shi, G. Y., and Wu, H. L. (2010) Downregulation of thrombomodulin, a novel target of Snail, induces tumorigenesis through epithelial-mesenchymal transition. Mol Cell Biol 30, 4767-4785
20. Shi, C. S., Shi, G. Y., Chang, Y. S., Han, H. S., Kuo, C. H., Liu, C., Huang, H. C., Chang, Y. J., Chen, P. S., and Wu, H. L. (2005) Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation 111, 1627-1636
21. Nahrendorf, M., Swirski, F. K., Aikawa, E., Stangenberg, L., Wurdinger, T., Figueiredo, J. L., Libby, P., Weissleder, R., and Pittet, M. J. (2007) The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 204, 3037-3047
22. Mosser, D. M., and Edwards, J. P. (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8, 958-969
23. Gordon, S., and Taylor, P. R. (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5, 953-964
24. Janeway, C. A., Jr., and Medzhitov, R. (2002) Innate immune recognition. Annu Rev Immunol 20, 197-216
25. Guha, M., and Mackman, N. (2001) LPS induction of gene expression in human monocytes. Cell Signal 13, 85-94
26. Ozinsky, A., Underhill, D. M., Fontenot, J. D., Hajjar, A. M., Smith, K. D., Wilson, C. B., Schroeder, L., and Aderem, A. (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A 97, 13766-13771
27. Brown, G. D. (2006) Dectin-1: a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol 6, 33-43
28. Medzhitov, R. (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1, 135-145
29. Robinson, M. J., Sancho, D., Slack, E. C., LeibundGut-Landmann, S., and Reis e Sousa, C. (2006) Myeloid C-type lectins in innate immunity. Nat Immunol 7, 1258-1265
30. Trinchieri, G., and Sher, A. (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7, 179-190
31. Aderem, A., and Underhill, D. M. (1999) Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 17, 593-623
32. Tse, S. M., Furuya, W., Gold, E., Schreiber, A. D., Sandvig, K., Inman, R. D., and Grinstein, S. (2003) Differential role of actin, clathrin, and dynamin in Fc gamma receptor-mediated endocytosis and phagocytosis. J Biol Chem 278, 3331-3338
33. Fraser, I. P., Koziel, H., and Ezekowitz, R. A. (1998) The serum mannose-binding protein and the macrophage mannose receptor are pattern recognition molecules that link innate and adaptive immunity. Semin Immunol 10, 363-372
34. Balkwill, F., and Mantovani, A. (2001) Inflammation and cancer: back to Virchow? Lancet 357, 539-545
35. Allavena, P., Sica, A., Solinas, G., Porta, C., and Mantovani, A. (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66, 1-9
36. Coussens, L. M., and Werb, Z. (2002) Inflammation and cancer. Nature 420, 860-867
37. Nakayama, T., Yao, L., and Tosato, G. (2004) Mast cell-derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors. J Clin Invest 114, 1317-1325
38. Bingle, L., Brown, N. J., and Lewis, C. E. (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196, 254-265
39. Pollard, J. W. (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4, 71-78
40. Balkwill, F., Charles, K. A., and Mantovani, A. (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211-217
41. Sica, A., Allavena, P., and Mantovani, A. (2008) Cancer related inflammation: the macrophage connection. Cancer Lett 267, 204-215
42. Talks, K. L., Turley, H., Gatter, K. C., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., and Harris, A. L. (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157, 411-421
43. Knowles, H. J., and Harris, A. L. (2007) Macrophages and the hypoxic tumour microenvironment. Front Biosci 12, 4298-4314
44. Schioppa, T., Uranchimeg, B., Saccani, A., Biswas, S. K., Doni, A., Rapisarda, A., Bernasconi, S., Saccani, S., Nebuloni, M., Vago, L., Mantovani, A., Melillo, G., and Sica, A. (2003) Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198, 1391-1402
45. Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S., and Ruco, L. (1992) The origin and function of tumor-associated macrophages. Immunol Today 13, 265-270
46. Mantovani, A., Schioppa, T., Porta, C., Allavena, P., and Sica, A. (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25, 315-322
47. Balkwill, F. (2004) Cancer and the chemokine network. Nat Rev Cancer 4, 540-550
48. Mantovani, A., Sozzani, S., Locati, M., Allavena, P., and Sica, A. (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23, 549-555
49. Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., and Locati, M. (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25, 677-686
50. Solinas, G., Germano, G., Mantovani, A., and Allavena, P. (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86, 1065-1073
51. Gordon, S., and Martinez, F. O. (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32, 593-604
52. Lawrence, T., and Natoli, G. (2011) Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11, 750-761
53. Sica, A., Larghi, P., Mancino, A., Rubino, L., Porta, C., Totaro, M. G., Rimoldi, M., Biswas, S. K., Allavena, P., and Mantovani, A. (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18, 349-355
54. Underhill, D. M., and Ozinsky, A. (2002) Phagocytosis of microbes: complexity in action. Annu Rev Immunol 20, 825-852
55. Henneke, P., and Golenbock, D. T. (2004) Phagocytosis, innate immunity, and host-pathogen specificity. J Exp Med 199, 1-4
56. Mosser, D. M. (2003) The many faces of macrophage activation. J Leukoc Biol 73, 209-212
57. Biswas, S. K., Gangi, L., Paul, S., Schioppa, T., Saccani, A., Sironi, M., Bottazzi, B., Doni, A., Vincenzo, B., Pasqualini, F., Vago, L., Nebuloni, M., Mantovani, A., and Sica, A. (2006) A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107, 2112-2122
58. Umemura, N., Saio, M., Suwa, T., Kitoh, Y., Bai, J., Nonaka, K., Ouyang, G. F., Okada, M., Balazs, M., Adany, R., Shibata, T., and Takami, T. (2008) Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J Leukoc Biol 83, 1136-1144
59. Solinas, G., Schiarea, S., Liguori, M., Fabbri, M., Pesce, S., Zammataro, L., Pasqualini, F., Nebuloni, M., Chiabrando, C., Mantovani, A., and Allavena, P. (2010) Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol 185, 642-652
60. Sica, A., Schioppa, T., Mantovani, A., and Allavena, P. (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42, 717-727
61. Colombo, M. P., and Mantovani, A. (2005) Targeting myelomonocytic cells to revert inflammation-dependent cancer promotion. Cancer Res 65, 9113-9116
62. An, T., Sood, U., Pietruk, T., Cummings, G., Hashimoto, K., and Crissman, J. D. (1987) In situ quantitation of inflammatory mononuclear cells in ductal infiltrating breast carcinoma. Relation to prognostic parameters. Am J Pathol 128, 52-60
63. Tsutsui, S., Yasuda, K., Suzuki, K., Tahara, K., Higashi, H., and Era, S. (2005) Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep 14, 425-431
64. Nowicki, A., Szenajch, J., Ostrowska, G., Wojtowicz, A., Wojtowicz, K., Kruszewski, A. A., Maruszynski, M., Aukerman, S. L., and Wiktor-Jedrzejczak, W. (1996) Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int J Cancer 65, 112-119
65. Robinson, S. C., Scott, K. A., Wilson, J. L., Thompson, R. G., Proudfoot, A. E., and Balkwill, F. R. (2003) A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res 63, 8360-8365
66. Gazzaniga, S., Bravo, A. I., Guglielmotti, A., van Rooijen, N., Maschi, F., Vecchi, A., Mantovani, A., Mordoh, J., and Wainstok, R. (2007) Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol 127, 2031-2041
67. Siegert, A., Denkert, C., Leclere, A., and Hauptmann, S. (1999) Suppression of the reactive oxygen intermediates production of human macrophages by colorectal adenocarcinoma cell lines. Immunology 98, 551-556
68. Martinez, F. O., Sica, A., Mantovani, A., and Locati, M. (2008) Macrophage activation and polarization. Front Biosci 13, 453-461
69. Mantovani, A., Allavena, P., and Sica, A. (2004) Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression. Eur J Cancer 40, 1660-1667
70. Dirkx, A. E., Oude Egbrink, M. G., Wagstaff, J., and Griffioen, A. W. (2006) Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol 80, 1183-1196
71. Torisu, H., Ono, M., Kiryu, H., Furue, M., Ohmoto, Y., Nakayama, J., Nishioka, Y., Sone, S., and Kuwano, M. (2000) Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha. Int J Cancer 85, 182-188
72. Nishie, A., Ono, M., Shono, T., Fukushi, J., Otsubo, M., Onoue, H., Ito, Y., Inamura, T., Ikezaki, K., Fukui, M., Iwaki, T., and Kuwano, M. (1999) Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5, 1107-1113
73. Salvesen, H. B., and Akslen, L. A. (1999) Significance of tumour-associated macrophages, vascular endothelial growth factor and thrombospondin-1 expression for tumour angiogenesis and prognosis in endometrial carcinomas. Int J Cancer 84, 538-543
74. Hanada, T., Nakagawa, M., Emoto, A., Nomura, T., Nasu, N., and Nomura, Y. (2000) Prognostic value of tumor-associated macrophage count in human bladder cancer. Int J Urol 7, 263-269
75. Leek, R. D., Lewis, C. E., Whitehouse, R., Greenall, M., Clarke, J., and Harris, A. L. (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56, 4625-4629
76. Giraudo, E., Inoue, M., and Hanahan, D. (2004) An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114, 623-633
77. Grimshaw, M. J., and Balkwill, F. R. (2001) Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation--a potential mechanism. Eur J Immunol 31, 480-489
78. DeNardo, D. G., Andreu, P., and Coussens, L. M. (2010) Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev 29, 309-316
79. DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., Gallagher, W. M., Wadhwani, N., Keil, S. D., Junaid, S. A., Rugo, H. S., Hwang, E. S., Jirstrom, K., West, B. L., and Coussens, L. M. (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1, 54-67
80. De Palma, M., and Lewis, C. E. (2011) Cancer: Macrophages limit chemotherapy. Nature 472, 303-304
81. Grey, S. T., and Hancock, W. W. (1996) A physiologic anti-inflammatory pathway based on thrombomodulin expression and generation of activated protein C by human mononuclear phagocytes. J Immunol 156, 2256-2263
82. Kim, H. K., Kim, J. E., Chung, J., Kim, Y. T., Kang, S. H., Han, K. S., and Cho, H. I. (2007) Lipopolysaccharide down-regulates the thrombomodulin expression of peripheral blood monocytes: effect of serum on thrombomodulin expression in the THP-1 monocytic cell line. Blood Coagul Fibrinolysis 18, 157-164
83. Smith, P. K., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J., and Klenk, D. C. (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150, 76-85
84. Clausen, B. E., Burkhardt, C., Reith, W., Renkawitz, R., and Forster, I. (1999) Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res 8, 265-277
85. Swirski, F. K., Nahrendorf, M., Etzrodt, M., Wildgruber, M., Cortez-Retamozo, V., Panizzi, P., Figueiredo, J. L., Kohler, R. H., Chudnovskiy, A., Waterman, P., Aikawa, E., Mempel, T. R., Libby, P., Weissleder, R., and Pittet, M. J. (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612-616
86. Luo, Y., Zhou, H., Krueger, J., Kaplan, C., Lee, S. H., Dolman, C., Markowitz, D., Wu, W., Liu, C., Reisfeld, R. A., and Xiang, R. (2006) Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 116, 2132-2141
87. Takagi, T., Taguchi, O., Toda, M., Ruiz, D. B., Bernabe, P. G., D'Alessandro-Gabazza, C. N., Miyake, Y., Kobayashi, T., Aoki, S., Chiba, F., Yano, Y., Conway, E. M., Munesue, S., Yamamoto, Y., Yamamoto, H., Suzuki, K., Takei, Y., Morser, J., and Gabazza, E. C. (2011) Inhibition of allergic bronchial asthma by thrombomodulin is mediated by dendritic cells. Am J Respir Crit Care Med 183, 31-42
88. Jones, G. E., Prigmore, E., Calvez, R., Hogan, C., Dunn, G. A., Hirsch, E., Wymann, M. P., and Ridley, A. J. (2003) Requirement for PI 3-kinase gamma in macrophage migration to MCP-1 and CSF-1. Exp Cell Res 290, 120-131
89. Zhang, B., Ma, Y., Guo, H., Sun, B., Niu, R., Ying, G., and Zhang, N. (2009) Akt2 is required for macrophage chemotaxis. Eur J Immunol 39, 894-901
90. Allen, W. E., Zicha, D., Ridley, A. J., and Jones, G. E. (1998) A role for Cdc42 in macrophage chemotaxis. J Cell Biol 141, 1147-1157
91. Allen, W. E., Jones, G. E., Pollard, J. W., and Ridley, A. J. (1997) Rho, Rac and Cdc42 regulate actin organization and cell adhesion in macrophages. J Cell Sci 110 ( Pt 6), 707-720
92. Tsai, C. S., Tsai, Y. T., Lin, C. Y., Lin, T. C., Huang, G. S., Hong, G. J., and Lin, F. Y. (2010) Expression of thrombomodulin on monocytes is associated with early outcomes in patients with coronary artery bypass graft surgery. Shock 34, 31-39
93. Ma, C. Y., Shi, G. Y., Shi, C. S., Kao, Y. C., Lin, S. W., and Wu, H. L. (2012) Monocytic Thrombomodulin Triggers LPS- and Gram-Negative Bacteria-Induced Inflammatory Response. J Immunol 188, 6328-6337
94. Sica, A., Saccani, A., Borsatti, A., Power, C. A., Wells, T. N., Luini, W., Polentarutti, N., Sozzani, S., and Mantovani, A. (1997) Bacterial lipopolysaccharide rapidly inhibits expression of C-C chemokine receptors in human monocytes. J Exp Med 185, 969-974
95. Sozzani, S., Ghezzi, S., Iannolo, G., Luini, W., Borsatti, A., Polentarutti, N., Sica, A., Locati, M., Mackay, C., Wells, T. N., Biswas, P., Vicenzi, E., Poli, G., and Mantovani, A. (1998) Interleukin 10 increases CCR5 expression and HIV infection in human monocytes. J Exp Med 187, 439-444
96. Fleetwood, A. J., Lawrence, T., Hamilton, J. A., and Cook, A. D. (2007) Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol 178, 5245-5252
97. Zabel, B. A., Ohyama, T., Zuniga, L., Kim, J. Y., Johnston, B., Allen, S. J., Guido, D. G., Handel, T. M., and Butcher, E. C. (2006) Chemokine-like receptor 1 expression by macrophages in vivo: regulation by TGF-beta and TLR ligands. Exp Hematol 34, 1106-1114
98. Lin, S.-Y., Makino, K., Xia, W., Matin, A., Wen, Y., Kwong, K. Y., Bourguignon, L., and Hung, M.-C. (2001) Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nature Cell Biology 3, 802-808
99. Andersson, U., and Tracey, K. J. (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol 29, 139-162
100. Smith, J. A. (1994) Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol 56, 672-686
101. Pham, C. T. (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6, 541-550
102. Brocker, E. B., Zwadlo, G., Holzmann, B., Macher, E., and Sorg, C. (1988) Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. Int J Cancer 41, 562-567
103. Gregory, A. D., and Houghton, A. M. (2011) Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res 71, 2411-2416
104. Fridlender, Z. G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L., Worthen, G. S., and Albelda, S. M. (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell 16, 183-194