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1 G-CSF (Granuocyte Colony Stimulating Factor) Granulocyte Colony Stimulating Factor (G-CSF) Attenuates 2,4,6-Trinitrobenzene Sulfonic Acid (TNBS)-induced Colitis in Mice Eun-Young Choi 1, Chang-Duk Jun 1, Jae-Min Oh 2, Yu-Rim Kim 2, Soo-Teik Lee 3 and Sang-Wook Kim 3 1 Department of Physiology, Kyungpook National University School of Medicine, Daegu, 2 Department of Anatomy, Wonkwang University School of Medicine, Iksan, 3 Department of Internal Medicine, Chonbuk National University School of Medicine, Jeonju, Korea ABSTRACT Background: Granulocyte colony stimulating factor (G-CSF) is known as a cytokine central to the hematopoiesis of blood cells and to modulate their cellular functions. Besides granulocytes and their precursors, monocytes/macrophages and endothelial cells are direct target cells of G-CSF action. G-CSF influences immune cells in an antiinflammatory way. Methods: To evaluate whether G-CSF has a potential for preventing or ameliorating diseases characterized by mucosal inflammation, we used a mouse model with trinitrobenzene sulfonic acid (TNBS)-induced inflammatory colitis. To the mice model G-CSF was administrated daily by intraperitoneal injection. Macroscopic evaluation and immunohistochemical analysis of colonic tissues were performed. Results: Recombinant human G-CSF significantly inhibited LPS-induced TNF- mrna expression in THP-1 cells. As for in vivo relevance, G-CSF dramatically reduced the weight loss of mice, colonic damage, and mucosal ulceration that characterize TNBS colitis. Moreover, G-CSF suppressed the expression of tumor necrosis factor-, interleukin-1, and intercellular adhesion molecule-1 in TNBS colitis. Conclusion: Current results demonstrate that G-CSF may be an effective agent for the treatment of diseases characterized by mucosal inflammation. (Immune Network 2006;6(1):13-19) Key Words: G-CSF, inflammatory bowel diseases, inflammation, TNBS Immune Network 13

2 14 Eun-Young Choi, et al.

3 G-CSF Attenuates Inflammatory Bowel Diseases 15 LPS Time (h) TNF-α GAPDH + G-CSF Figure 1. G-CSF inhibits the expression of TNF- induced by LPS. THP-1 cells ( /ml) were pretreated with G-CSF (500 ng/ml) for 1 h, and then the cells were further incubated for 16 h with LPS (10 g/ml). Levels of TNF- mrna were determined by RT-PCR. This is a representative of three separate experiments. A Weight (g) 26 Vehicle TNBS G-CSF 24 G-CSF+TNBS B Macroscopic Score 계열 Time (days) 1 0 TNBS G-CSF Figure 2. G-CSF ameliorates the clinical and macroscopic features of TNBS-induced colitis. Colitis was induced by rectal administration of 2 doses (separated by a 7-day interval) of TNBS in 50% ethanol. Mice treated with 50% ethanol alone were used as controls. G-CSF (250 g/kg) was injected intraperitoneally everyday 1 day (-1) before and after TNBS administration. All mice were sacrificed on day 9 after the first TNBS administration, and the clinical evaluation and severity were monitored by mouse weight changes. Each point represents the mean±sd from 5 separate experiments (5 mice/group/experiment).

16 Eun-Young Choi, et al. A B Histologic Score 10 8 6 4 2 0 TNBS - + - + G-CSF - - + + Figure 3. G-CSF ameliorates the histopathologic features of TNBS-induced colitis.

4 16 Eun-Young Choi, et al. A B Histologic Score TNBS G-CSF Figure 3. G-CSF ameliorates the histopathologic features of TNBS-induced colitis. The histopathologic signs were further estimated with the mice described in Figure 4. Photomicrographs of colon sections after treatment with ethanol, TNBS, G-CSF, and G-CSF+TNBS, on day 9 after the induction of colitis with TNBS are shown (original magnification 100 ) (A). Histopathologic scoring is shown (B). Results are the mean±sd from 5 mice per group.

5 G-CSF Attenuates Inflammatory Bowel Diseases 17 Figure 4. G-CSF reduces the expression of TNF-α IL-1β, and ICAM1 in colonic mucosa of TNBS colitis. Tissue sections from experimental groups (control group, TNBS- and/ or G-CSF-treated groups) were incubated with primary antibodies (αtnf-α, α-il-1β, and α-icam- 1). The slides were then incubated with anti-rabbit biotinylated secondary antibody and colorized by ABS/hematoxylin (original magnification 100). 모델을 이용한 실험에서도 증명이 되었다. 예를 들면, 랫 트에서 LPS로 유도된 독성을 G-CSF가 전신성 TNF-α를 억제함에 따라 예방할 수 있음을 보고하였다(14). 또한 마우스에서 LPS로 유도된 IL-18 및 IFN-γ 생성을 G-CSF 전처리로 감소시켰다(22). 또 다른 보고에 따르면, 마우 스에서 G-CSF 전처리 시 LPS로 유도되는 IL-10 및 monocyte chemoattractant protein-1 의 분비가 증가되는 반면, IL-1β, IL-6 및 IL-8의 분비에는 영향을 주지 않았다(23).

6 18 Eun-Young Choi, et al. 1. Mascheretti S, Schreiber S: Genetic testing in Crohn disease: utility in individualizing patient management. Am J Pharmacogenomics 5; , Schmidt C, Stallmach A: Etiology and pathogenesis of inflammatory bowel disease. Minerva Gastroenterol Dietol 51; , Kim SW, Choi SC, Choi EY, Kim KS, Oh JM, Lee HJ, Oh HM, Kim S, Oh BS, Kimm KC, Lee MH, Seo GS, Kim TH, Oh HC, Woo WH, Kim YS, Pae HO, Park DS, Chung HT, Jun CD: Catalposide, a compound isolated from catalpa ovata, attenuates induction of intestinal epithelial proinflammatory gene expression and reduces the severity of trinitrobenzene sulfonic Acid-induced colitis in mice. Inflamm Bowel Dis 10; , Lee HJ, Choi SC, Lee MH, Oh HM, Choi EY, Choi EJ, Yun KJ, Seo GS, Kim SW, Lee JG, Han WC, Park KI, Jun CD: Increased expression of MIP-3alpha/CCL20 in peripheral blood mononuclear cells from patients with ulcerative colitis and its down-regulation by sulfasalazine and glucocorticoid treatment. Inflamm Bowel Dis 11; , Yamaguchi T, Ihara K, Matsumoto T, Tsutsumi Y, Nomura A, Ohga S, Hara T: Inflammatory bowel disease-like colitis in glycogen storage disease type 1. Inflamm Bowel Dis 7; , Melis D, Parenti G, Della Casa R, Sibilio M, Berni Canani R, Terrin G, Cucchiara S, Andria G: Crohn s-like ileo-colitis in patients affected by glycogen storage disease Ib: two years follow-up of patients with a wide spectrum of gastrointestinal signs. Acta Paediatr 92; , Baldwin GC, Chung GY, Kaslander C, Esmail T, Reisfeld RA, Golde DW: Colony-stimulating factor enhancement of myeloid effector cell cytotoxicity towards neuroectodermal tumour cells. Br J Haematol 83; , Carulli G: Effects of recombinant human granulocyte colonystimulating factor administration on neutrophil phenotype and functions. Haematologica 82; , Tamamori Y, Sawada T, Nishihara T, Yamashita Y, Ohira M, Ho JJ, Kim YS, Hirakawa YS, Chung K: Granulocytecolony stimulating factor enhances chimeric antibody Nd2 dependent cytotoxicity against pancreatic cancer mediated by polymorphonuclear neutrophils. Int J Oncol 21; , Shimoda K, Okamura S, Harada N, Kondo S, Okamura T, Niho Y: Identification of a functional receptor for granulocyte colony-stimulating factor on platelets. J Clin Invest 91; , Bussolino F, Colotta F, Bocchietto E, Guglielmetti A, Mantovani A: Recent developments in the cell biology of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor: activities on endothelial cells. Int J Clin Lab Res 23;8-12, Boneberg EM, Hareng L, Gantner F, Wendel A, Hartung T: Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma. Blood 95; , Morikawa K, Morikawa S, Nakamura M, Miyawaki T: Characterization of granulocyte colony-stimulating factor receptor expressed on human lymphocytes. Br J Haematol 118; , Gorgen I, Hartung T, Leist M, Niehorster M, Tiegs G, Uhlig S, Weitzel F, Wendel A: Granulocyte colony-stimulating factor treatment protects rodents against lipopolysaccharideinduced toxicity via suppression of systemic tumor necrosis factor-alpha. J Immunol 149; , Niho Y, Niiro H, Tanaka Y, Nakashima H, Otsuka T: Role of IL-10 in the crossregulation of prostaglandins and cytokines in monocytes. Acta Haematol 99; , Vilaseca J, Salas A, Guarner F, Rodriguez R, Martinez M, Malagelada JR: Dietary fish oil reduces progression of chronic inflammatory lesions in a rat model of granulomatous colitis. Gut 31; , Rogler G, Andus T: Cytokines in inflammatory bowel disease. World J Surg 22; , Richards MK, Liu F, Iwasaki H, Akashi K, Link DC: Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood 102; , Barreda DR, Hanington PC, Belosevic M: Regulation of mye-

7 G-CSF Attenuates Inflammatory Bowel Diseases 19 loid development and function by colony stimulating factors. Dev Comp Immunol 28; , Zhu QS, Xia L, Mills GB, Lowell CA, Touw IP, Corey SJ: G-CSF induced reactiveoxygen species involves Lyn-PI 3-kinase-Akt and contributes to myeloid cell growth. Blood Nov 10, 2005 [Epub ahead of print] 21. Nishiki S, Hato F, Kamata N, Sakamoto E, Hasegawa T, Kimura-Eto A, Hino M, Kitagawa S: Selective activation of STAT3 in human monocytes stimulated by G-CSF: implication in inhibition of LPS-induced TNF-alpha production. Am J Physiol Cell Physiol 286;C , Shaklee CL, Guo J, Faggioni R, Fantuzzi G, Senaldi G: Pretreatment with granulocyte-colony stimulating factor decreases lipopolysaccharide-induced interferon-gamma production in mice in association with the production of interleukin-18. Cytokine 25; , Saito M, Kiyokawa N, Taguchi T, Suzuki K, Sekino T, Mimori K, Suzuki T, Nakajima H, Katagiri YU, Fujimura J, Fujita H, Ishimoto K, Yamashiro Y, Fujimoto J: Granulocyte colony-stimulating factor directly affects human monocytes and modulates cytokine secretion. Exp Hematol 30; , Egi H, Hayamizu K, Yoshimitsu M, Shimamoto F, Oishi K, Ohmori I, Okajima M, Asahara T: Regulation of T helper type-1 immunity in hapten-induced colitis by host pretreatment with granulocyte colony-stimulating factor. Cytokine 23; 23-30, 2003

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract