發炎為受微生物侵入或組織受傷時，所產生有利於宿主的保護反應
，主要作用在於修復組織的結構與功能。巨噬細胞(macrophage)是生物體內重要的免疫細胞，它能藉著釋放許多促發炎的調節分子來對病原體作出反應，包括了一氧化氮(nitric oxide, NO)和前列腺素(prostaglandin)。它在發炎反應中也扮演著重要的角色。利用脂多醣體(lipopolysaccharide, LPS)。誘發巨噬細胞活化已被廣泛使用於鑑別許多物質是否有抗發炎的效果。胸腺素α 1(thymosin α 1, Tα1)是胸腺所產生的多種類物質之一，它具有增強T細胞(T cell)功能和調節免疫平衡等作用，其序列為前胸腺素α(prothymosin α, ProTα)的前28個胺基酸所組成。我們的研究結果顯示，在LPS活化小鼠RAW264.7巨噬細胞株的狀態下，Tα1和
glutathione S-transferase (GST)之融合蛋白(GST-Tα1)有抑制NO及tumor necrosis factor-α (TNF-α)、interleukin-6 (IL-6)過量表現的效果。經由反轉錄聚合連鎖反應(RT-PCR)的分析，我們也發現GST-Tα1會抑制inducible NO synthase (iNOS)、TNF-α和Cyclooxygenases-2 (COX-2)的mRNA表現。在接上GST-Tα1的金奈米複合物上，也有類似的情形發生。因此，我們推測GST-Tα1和GST-Tα1的金奈米(nanogold)複合物在LPS活化小鼠RAW264.7巨噬細胞株的狀態下，應該有抑制發炎反應的效果存在。然而，長時間的發炎會導致許多疾病的產生，包括支氣管炎、胃炎、發炎性腸道疾病、多發性硬化症和類風濕性關節炎等。因此，使用GST-Tα1和GST-Tα1的金奈米複合物來治療各種跟發炎有關的疾病，可能是一個新的治療方向。

Inflammation is a beneficial host response to a foreign
challenge or tissue injury that leads ultimately to the restoration of normal tissue structure and function. Macrophages are the main proinflammatory cells that respond to invading pathogens by releasing many pro-inflammatory molecules, including nitric oxide (NO)and prostaglandins. They also play a central role in the inflammatory response.Lipopolyssacharide (LPS)-stimulated macrophages have usually been used for evaluating the
anti-inflammatory effects of various materials.Thymosin α 1 (Tα1)is a peptide produced by thymus. It can augment T cell fucction and it has immunomodulatory activities. Tα1, a 28 amino acid peptide derived by cleavage of prothymosin α (ProTα).In our study, we found that GST-Tα1 fusion protein (GST-Tα1) inhibited excessive production of inflammatory mediators, nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in LPS-stimulated murine RAW264.7 macrophages. Our results also showed that GST-Tα1 inhibited the excessive production of inducible nitric oxide synthase (iNOS), TNF-α, and COX-2 in mRNA expression, as determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. GST-Tα1- nanogold complex also possessed similar effects. These data suggest that GST-Tα1 exhibits potent anti-inflammatory effects on LPS-stimulated murine RAW264.7 macrophages. Prolonged inflammation contributes to the pathogenesis of many inflammatory diseases, including bronchitis, gastritis, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. These results suggest that the use of GST-Tα1 and GST-Tα1-nanogold complex may be a new therapeutic approach for various inflammatory diseases.

Baggiolini, M. (1998). Chemokines and leukocyte traffic. Nature 392, 565–568.
Beutler, B., Poltorak, A. (2000). The search for Lps:1993-1998. J Endotoxin Res 6, 269–293.
Beutler, B. (2003). Innate immune response to microbial poisons:discovery and function of the toll like receptors. Annu Rev Pharmacol Toxicol 43, 609–628.
Billich, A. (2002). Thymosin α1(SciClone Pharmaceuticals). Curr Opin Investig Drugs 3, 698–707
Bondeson, J. (1997). The mechanisms of action of disease-modifying antirheumatic drugs: a review with emphasis on macrophage signal transduction and the induction of proinflammatory cytokines. Gen Pharmacol 29, 127–150.
Chen, Y.H., Tsai, C.Y., Huang, P.Y., Chang, M.Y., Cheng, P.C., Chou, C.H., Chen, D.H., Wang, C.R., Shiau, A.L., Wu, C.L. (2007). Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model. Mol Pharm 4, 713–722
Connor, E.E., Mwamuka, J., Gole, A., Murphy, C.J., Wyatt, M.D. (2005). Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small 1, 325–327
Dayer, J.M. (2004). The process of identifying and understanding cytokines:from basic studies to treating rheumatic diseases. Best Pract Res Clin Rheumatol 18, 31–45.
Diehl, S., Rincon, M. (2002). The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol 39, 531–536.
Fichtner-Feigl, S., Fuss, I.J., Preiss, J.C., Strober, W., Kitani, A. (2005).Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-kappa B decoy oligonucleotides. J Clin Invest 115, 3057–3071.
Fujihara, M., Muroi, M., Muroi, Y., Ito, N., Suzuki, T. (1993). Mechanism of lipopolysaccharide-triggered junB activation in a mouse macrophage-like cell line (J774). J Biol Chem 268, 14898–14905.
Fujihara, M., Connolly, N., Ito, N., Suzuki, T. (1994a). Properties of protein kinase C isoforms (beta II, epsilon, and zeta) in a macrophage cell line (J774) and their roles in LPS-induced nitric oxide production. J Immunol 152, 1898–1906.
Goldstein, A.L., Guha, A., Zatz, M.M., Hardy, M.A., White, A. (1972). Purification and biological activity of thymosin, a hormone of the thymus gland. Proc Natl Acad Sci USA 69, 1800–1803.
Goldstein, A.L., Badamchian, M. (2004). Thymosins: chemistry and biological properties in health and disease. Expert Opin Biol Ther 4, 559–573.
Guha, M., Mackman, N. (2001). LPS induction of gene expression in human monocytes. Cell Signal 13, 85–94.
Hambleton, J., Weinstein, S.L., Lem, L., DeFranco, A.L. (1996). Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide stimulated macrophages. Proc Natl Acad Sci USA 93, 2774–2778.
Han, J., Lee, J.D., Bibbs, L., Ulevitch, R.J. (1994). A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808–811.
Herrera-Velit, P., Reiner, N.E. (1996). Bacterial lipopolysaccharide induces the association and coordinate activation of p53/56lyn and phosphatidyl- inositol 3-kinase in human monocytes. J Immunol 156, 1157–1165.
Hewett, J.A., Roth, R.A. (1993). Hepatic and extrahepatic pathobiology of bacterial lipopolysaccharides. Pharmacol Rev 45, 382–411.
Ishiguro, Y. (1999). Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis. J Gastroenterol 34, 66–74.
Jakway, J.P., DeFranco, A.L. (1986). Pertussis toxin inhibition of B cell and macrophage responses to bacterial lipopolysaccharide. Science 234, 743–746.
Klotz, L., Schmidt, M., Giese, T., Sastre, M., Knolle, P., Klockgether, T., Heneka, M.T. (2005). Proinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple
sclerosis patients. J Immunol 175, 4948–4955.
Knutsen, A.P., Freeman, J.J., Mueller, K.R., Roodman, S.T., Bouhasin, J.D. (1999). Thymosin-α1 stimulates maturation of CD34+ stem cells into CD3+4+ cells in an in vitro thymic epithelia organ coculture model.
Int J Immunopharmacol 21, 15–26
Kolb, H., Kolb-Bachofen, V. (1992). Nitric oxide: a pathogenic factor in autoimmunity. Immunol Today 13, 157–160.
Kubes, P., McCafferty, D.M. (2000). Nitric oxide and intestinal inflammation.
Am J Med 109, 150–158.
Levy, G.N. (1997). Prostaglandin H synthases, nonsteroidal anti-inflammatory drugs, and colon cancer. FASEB J 11, 234–247.
Low, T.L.K., Thurman, G.B., McAdoo, M., McClure, J., Rossio, J.L., Naylor, P.H., Goldstein, A.L. (1979). Isolation, characterization, and biological activities of thymosin α1 and polypeptide β1 from calf thymus. J Biol Chem 254, 981–986
MacMicking, J., Xie, Q.W., Nathan, C. (1997). Nitric oxide and macrophage function. Annu Rev Immunol 15, 323–350.
Moncada, S., Palmer, R.M.J., Higgs, E.A. (1992). Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacological Reviews 43, 109–142.
Guzik, T.J., Korbut, R., Adamek-Guzik, T. (2003). Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol 54, 469–487
Muroi, M., Suzuki, T. (1993). Role of protein kinase A in LPS-induced activation of NF-nB proteins of a mouse macrophage-like cell line, J774. Cell Signal 5, 289–298.
Nathan, C. (1992). Nitric oxide as a secretory product of mammalian cells.FASEB J 6, 3051–3064.
Nathan, C., Xie, Q.W. (1994). Regulation of biosynthesis of nitric oxide.J Biol Chem 269, 13725–13728.
Paciotti, G.F., Myer, L., Weinreich, D., Goia, D., Pavel, N., McLaughlin, R.E., Tamarkin, L. (2004). Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Deliv 11, 169–183.
Paciotti, G.F., Kingston, D.G.I., Tamarkin, L.(2006) .Colloidal gold nanoparticles: a novel nanoparticle platform for developing multifunctional tumor-targeted drug delivery vectors. Drug Dev Res 67, 47–54.
Poltorak, A., He, X., Smirnova, I. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088.
Ponchel, F., Morgan, A.W., Bingham, S.J., Quinn, M., Buch, M., Verburg, R.J., Henwood, J., Douglas, S.H., Masurel, A., Conaghan, P., et al. (2002). Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis. Blood 100, 4550–4556.
Qureshi, S.T., Lariviere, L., Leveque, G., Clermont, S., Moore, K.J., Gros, P.,et al. (1999). Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 189, 615–625.
Raetz, C.R. (1990). Biochemistry of endotoxins. Annu Rev Biochem 59, 129–170.
Rice, T.W., Bernard, G.R. (2005). Therapeutic intervention and targets for sepsis. Annu Rev Med 56, 225–248.
Romani, L., Bistoni, F., Gaziano, R., Bozza, S., Montagnoli, C., Perruccio, K., Pitzurra, L., Bellocchio, S., Velardi, A., Rasi, G., Di Francesco, P., Garaci, E. (2004). Thymosin α1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood 103, 4232–4239
Skirtach, A.G., Javier, A.M., Kreft, O., Kohler, K., Alberola, A.P., Mohwald, H., Parak, W.J., Sukhorukov, G.B. (2006). Laser-induced release of encapsulated materials inside living cells, Angew Chem Int Ed 45, 4612–4617.
Sodhi, A., Paul, S. (2002). Involvement of mitogen-activated protein kinases in the signal transduction pathway of bone marrow-derived macrophage activation in response to in vitro treatment with thymosin alpha 1.
Int Immunopharmacol 2, 47–58.
Takahashi, M., Mutoh, M., Shoji, Y., Sato, H., Kamanaka, Y., Naka, M., Maruyama, T., Sugimura, T., Wakabayashi, K. (2006). Suppressive effect of an inducible nitric oxide inhibitor, ONO-1714, on AOM-induced rat colon carcinogenesis. Nitric Oxide 14, 130–136.
Vernooy, J.H., Dentener, M.A., van Suylen, R.J., Buurman, W.A., Wouters, E.F. (2002). Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology. Am J Respir Cell Mol Biol 26, 152–159.
Walsh, N.C., Crotti, T.N., Goldring, S.R., Gravallese, E.M. (2005).Rheumatic diseases: the effects of inflammation on bone. Immunol Rev 208, 228–251.
Wang, S.S., Makofske, R., Bach, A., Merrifield, R.B. (1980). Automated solid phase synthesis of thymosin α1. Int J Peptide Protein Res 15, 1–4.
Watson, W.H., Zhao, Y., Chawla, R.K. (1999). S-adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha. Biochem J 342, 21–25.
Weinstein, S.L., Sanghera, J.S., Lemke, K., DeFranco, A.L., Pelech, S.L. (1992). Bacterial lipopolysaccharide induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in macrophages. J Biol Chem 267, 14955–14962.