J. Milk Sci. Biotechnol. Vol. 34. No. 1, pp. 1~7 (2016) Growth Factors and Their Function in Colostrum: A Review Gereltuya Renchinkhand, Ji Yoon Son a

Size: px

Start display at page:

Download "J. Milk Sci. Biotechnol. Vol. 34. No. 1, pp. 1~7 (2016) Growth Factors and Their Function in Colostrum: A Review Gereltuya Renchinkhand, Ji Yoon Son a"

예준 감
5 years ago
Views:

J. Milk Sci. Biotechnol. Vol. 34. No. 1, pp. 1~7 (2016) Growth Factors and Their Function in Colostrum: A Review Gereltuya Renchinkhand, Ji Yoon Son and Myoung Soo Nam * Lab.

1 J. Milk Sci. Biotechnol. Vol. 34. No. 1, pp. 1~7 (2016) Growth Factors and Their Function in Colostrum: A Review Gereltuya Renchinkhand, Ji Yoon Son and Myoung Soo Nam * Lab. of Milk Food Biochemistry and Biotechnology, College of Agriculture and Life Sciences, Chungnam National University, Daejeon 34134, Korea Abstract Colostrum, a nutrient-rich fluid produced by female mammals after giving birth, is the specific initial diet of mammalian neonates. Colostrum is important for the nutrition, growth, and development of newborn infants and contributes to the immunologic defense of neonates. It contains immunoglobulins, antimicrobial peptides, such as lactoferrin and lactoperoxidase, and other bioactive molecules, including growth factors, such as IGF (insulin-like growth factor), EGF (epithermal growth factor), TGF-β (transforming growth factor), and FGF (fibroblast growth factor). Bovine colostrum is a rich source of growth factors, which play a central role in wound healing. The biological activities of colostrum emphasize the relevance of the synergistic activity of growth factors to stimulate keratinocyte proliferation and migration, which are essential for tissue repair. Colostrum increases the expression of early differentiation markers, such as keratin 1 and 10 and involucrin, and late differentiation markers, including loricrin and filaggrin. Additionally, colostrum increases granulation tissue volume in the dermis, suggesting that it has a beneficial effect on wound healing. The therapeutic use of colostrum or individual peptides present in colostrum has a positive and curative influence on various gastrointestinal diseases. Keywords: colostrum, growth factor, neonate, proliferation, wound healing (colostrum) 48, (normal milk)..,,. * Corresponding author: Myoung Soo Nam, Lab. of Milk Food Biochemistry and Biotechnology, College of Agriculture and Life Sciences, Chungnam National University, Daejeon 34134, Korea. Tel: , Fax: , namsoo@ cnu.ac.kr (immune factors) (antimicrobial activity) (growth factor), immunoglobulins, lactoferrin, lysozyme, lactoperoxidase, cytokines(larson et al., 1977; Besser and Gay, 1994), IGF(insuline-like growth factor), EGF(epithermal growth factor), TGF-β(transforming growth factor), FGF(fibroblast growth factor) (Playford et al., 2000). IGF. EGF, TGF (Playford et al., 2000)., Nam (2002) 1

2 2 Journal of Milk Science & Biotechnology 제 34 권제 1 호 (2016) TGF-β1, Cho (2003) IGFs, Hwang (2004) IGF-1. Bae (2007) 1 20~30 kg, 1 5 kg,. 91%.,,., (Growth factor) peptide,. (Klagsburn, 1978), Klagsburn Neumann 1979.,,, (Sacerdote et al., 2013).,, IgA. /, (Pakkanen et al., 1997; Playford et al., 2000). Cox Bürk(1991) TGF-β2 polypeptide, Jin (1991) milk growth factor(mgf), TGF-β1 TGF-β2, TGF-β2 85%. 3) Epidermal Growth Factor(EGF) EGF (Plaut, 1993). 53, Brunners. 200 μg/l, 30~50 μg/l (Read et al., 1985), 3~5 μg/l(iacopetta et al., 1992).. Fig. 1 Table 1,. Fig. 1 FGF-β 180 pg/mg, GM-CSF 170 pg/mg, TGF-β 65 pg/mg, VEGF, TNF, PDGF bb, NGF 1) Insulin Like Growth Factor(IGF)-1, 2 (IGF-1; 50~2,000 μg/l, IGF-2; 200~600 μg/l),.,. 7.6 kd single polypeptide chain A, B, C, D 4 domain. Insulin D domain, C domain. IGF-1,2 receptor (Rathe et al., 2014). 2) Transforming Growth Factor beta(tgf-β1 and β2) ( ), T. (embryo), Fig. 1. Evaluation of growth factor (top) and cytokines (bottom) in the standardized bovine colostrum derivative (Sacerdote et al., J. Dairy Sci. Vol. 96)

초유에함유된성장인자와기능 : 총설 3 Table 1. Concentration of growth factors EGF IGF-1 IGF-2 TGF-β1 TGF-β2 Colostrum Milk Reference Human 200 μg/l 30~50 μg/l Bovine trace trace Playford et al.

3 초유에함유된성장인자와기능 : 총설 3 Table 1. Concentration of growth factors EGF IGF-1 IGF-2 TGF-β1 TGF-β2 Colostrum Milk Reference Human 200 μg/l 30~50 μg/l Bovine trace trace Playford et al. (2000) Human 18 μg/l - Bovine 50~2,0000 μg/l 10 μg/l Playford et al. (2000) Human 18 μg/l - Bovine 200~600 μg/l 10 μg/l Playford et al. (2000) Human - - Bovine 6.3 μg/l 1.5 μg/l Purup et al. (2007) Human - - Bovine 143 μg/l 21 μg/l Purup et al. (2007). Cytokine T, proinflammatory (Gaffen, 2011) (Krstic et al., 2012) IL pg/mg, IL-2 7 pg/mg, IFN-γ 6 pg/mg, IL-15, IL-9. Table 1. 2., ~ M.. (autocrine), (paracrine), (endocrin) (Fig. 2). (Coci and Sunshine, 2009). 3. Fig. 2. Autocrine, paracrine and endocrine properties of cytokines. The brain is illustrated as an example of an organ that responds to cytokines in an endocrine fashion (Coci and Sunshine, 2009). 1) In vitro, Human keratinocyte HaCaT cell line Kovacs (2009) HaCaT cell 5% 10% 24 HaCaT cell. 10% FBS HaCaT cell. 48 2%, 5%, 10%, 10% FBS., 20% Madin-Darby canine kidney epithelial cells(mdck, Klagsburn, 1980) mouse hybridoma cells (Pakkanen et al., 1992), HaCaT cell. Fig. 3 HaCaT cell, 5%, 10%, 105 FBS 24. DNA BrdU. Fig. 3 a, c, e, g BrdU incorporation assay, b, d, f, h

4 Journal of Milk Science & Biotechnology 제 34 권제 1 호 (2016) Fig. 4. Scratch assay on HaCaT cells in response to treatment with colostrum and 10% FBS (Kovacs et al., 2009).. 10% FBS (Fig.

BrdU incorporation assay (a, c, e, g) and parallel phase contrast microscopy (b, d, f, g) of HaCaT cells grown for 24 h in serum-free condition (a, b), in the presence of 5% (c, d), and 10%

2) In vivo, wound healing of rabbit ear model Fig. 5, Western blot. filaggrin loricrin. K1, K10, involucrin.,.. (a, b) 5%(59.8±2%) 10%(59.2±3.4%) (c, d, e, f) 10% FBS (66±9.2%). (Hironaka et al.

4 4 Journal of Milk Science & Biotechnology 제 34 권제 1 호 (2016) Fig. 4. Scratch assay on HaCaT cells in response to treatment with colostrum and 10% FBS (Kovacs et al., 2009).. 10% FBS (Fig. 4C) positive control 10%. Fig. 3. BrdU incorporation assay (a, c, e, g) and parallel phase contrast microscopy (b, d, f, g) of HaCaT cells grown for 24 h in serum-free condition (a, b), in the presence of 5% (c, d), and 10% colostrum (e, f) or 10% FBS (g, h). Percentage of BrdU positive HaCaT cells maintained without serum, kept in the presence of 5 and 10% colostrum or 10% FBS (Kovacs et al., 2009). 2) In vivo, wound healing of rabbit ear model Fig. 5, Western blot. filaggrin loricrin. K1, K10, involucrin.,.. (a, b) 5%(59.8±2%) 10%(59.2±3.4%) (c, d, e, f) 10% FBS (66±9.2%). (Hironaka et al., 1997; Playford et al., 1999; Torre et al., 2006; Purup et al., 2007; An et al., 2009). Fig. 4 HaCaT cell, 10%, 10% FBS actin. 10% (Fig. 4b), Fig. 5. Effect of colostrum on keratinocyte differentiation. Cell extracts were prepared at the indicated time points and Western blot was performed against several differentiation markers (Kwon et al., 2007).

5 초유에 함유된 성장인자와 기능: 총설 은 초유성분이 상처회복에 도움이 되는지 확인하기 위하여 토끼 귀를 시료로 사용하였다. 토끼 귀의 안쪽 면에 상처를 내고, 초유를 1일 1회씩 7일간 도포하고, 상처 회복을 관찰하였다. Fig. 6A와 같이 초유 처리군이 대조군에 비해 상 처회복이 현저히 증가되지는 않았다. 또한 Fig.

6C에 나타난 바와 같이 진피부에 형성되는 granulation tissue의 volume을 측정한 결과, 초유 처리군에서 20~30% 정도 증가하는 것으로 확인되었기에 초유가 상처회 복에 어느 정도 도움을 줄 수 있을 것으로 판단된다. 이러한 결과는 초유가 각질형성세포 분화 초기 및 후기에 신호전달 계를 활성화하기 때문으로 생각된다.

또한 ERK1/2 및 p38과 같은 mitogen activated protein kinase (MAPK)의 활 성화가 각질형성세포 분화에 중요한 역할을 하는 것으로 알 려졌다(Eckert et al., 2002; Efimova et al., 2003). Fig.

5 5 초유에 함유된 성장인자와 기능: 총설 은 초유성분이 상처회복에 도움이 되는지 확인하기 위하여 토끼 귀를 시료로 사용하였다. 토끼 귀의 안쪽 면에 상처를 내고, 초유를 1일 1회씩 7일간 도포하고, 상처 회복을 관찰하였다. Fig. 6A와 같이 초유 처리군이 대조군에 비해 상 처회복이 현저히 증가되지는 않았다. 또한 Fig. 6B에 나타난 바와 같이, 표피의 각질현성세포 및 진피의 섬유아세포 분열 에 대한 효과는 뚜렷하게 세포분열 증가 효과가 나타나지 않 았다. 그러나 Fig. 6C에 나타난 바와 같이 진피부에 형성되는 granulation tissue의 volume을 측정한 결과, 초유 처리군에서 20~30% 정도 증가하는 것으로 확인되었기에 초유가 상처회 복에 어느 정도 도움을 줄 수 있을 것으로 판단된다. 이러한 결과는 초유가 각질형성세포 분화 초기 및 후기에 신호전달 계를 활성화하기 때문으로 생각된다. Calcium과 같은 각질형 성 분화촉진 인자는 protein kinase C(PKC)를 활성화 시키고, 하위 단계의 신호전달계에 영향을 주는 것으로 보고되어졌 다(Bollag et al., 1993; O'Driscoll et al., 1994). 또한 ERK1/2 및 p38과 같은 mitogen activated protein kinase (MAPK)의 활 성화가 각질형성세포 분화에 중요한 역할을 하는 것으로 알 려졌다(Eckert et al., 2002; Efimova et al., 2003). Fig. 6 괴사성 소장결장염과 EGF 괴사성 소장결장염은 영유아의 생명에 위험을 주는 심각 한 질병으로 소장과 대장에 심각한 괴사를 야기한다. 병인학 은 불명확하지만 많은 위험 요소가 있는데, 조산, 장 감염, 장 의 국부적 혈액 부족, 비정상적인 면역반응 등이 있다. 영유 아에서 EGF의 연속적인 투여 결과, 현저하게 장의 조직학적 으로 회복 효과가 나타났다(Fig. 7). 4. Fig. 7. Hematoxylm and eosin stain of small intestinal biopsies of a child with necrotizing enterocolitis (200 magnification) before (left) and 7 d after (right) infusion of epidermal growth factor. Before therapy the mucosa is virtually completely uncerated and after therapy the mucosa is almost completely regenerated (Playford et al., 2000). 요 약 젖소 초유에는 성장인자가 풍부하게 함유되어 있는데, 상 처 치유에 중요한 역할을 하고, 초유의 생리활성 기능을 담당 하고 있다. Tyrosine kinase receptor의 활성을 유도하는 성장 인자가 특이적으로 관여하여 세포의 분화, 면역기능, 신경기 능 등 세포간 상호작용에 관여하는 EGFR(상피증식인자 수 용체)와 FGFR(섬유아세포 증식인자)가 있다. 또한 VEGFR (혈관내피 증식인자)와 PDGF(혈소판유래 증식인자)도 존재 한다. 조직회복을 위한 각질세포 분화와 세포의 이행에 성장 인자가 상승효과를 나타내었고, 초유 또는 초유에 포함된 성 장인자 peptide들은 장관질환 치료에 효과가 있으므로 치료 제로 이용 가능성을 보여주었다. Fig. 6. Effect of colostrum on wound healing. (A) Sections were prepared with paraffin, and stained with hematoxylin-eosin (H&E stain). (B) Immunohistochemical staining was carried out with anti-pcna antibody. (C) Granulation tissue volume was measured using image analysis software (Kwon et al., 2007).

6 6 Journal of Milk Science & Biotechnology 제 34 권제 1 호 (2016) 1. An, M. J., Cheon, J. H., Kim, S. W., Park, J. J., Moon, C. M., Han, S. Y., Kim, E. S., Kim, T. I. and Kim, W. H Bovine colostrum inhibits nuclear factor kappabmediated proinflammatory cytokine expression in intestinal epithelial cells. Nutr. Res. 29: Bae, H. C., Renchinthand, G., Na, S. H., Choi, S. H. and Nam, M. S Studies on situation and utilization of domestic colostrum. Kor. J. Food Sci. Ani. Resour. 27: Besser, T. E. and Gay, C. C The importance of coloctrum to the health of the neonatal calf. Vet. Clin. N. Am-Food Anim. Practice. 10: Bollag, W. B., Ducote, J. and Harmon, C. S Effects of the selective protein kinase C inhibitor, ro , on the proliferation of cultured mouse epidermal keratinocytes. J. Invest. Dermatol. 100: Cho, Y. H., Lee, S. W., Chung, M. S., Baek, S. H., Jekal, S. J. and Park, G. Y Safety evaluation of IGFs separated and refined from colostrum. Kor. J. Food Sci. Ani. Resour. 23: Coico, R. and Sunshine, G Immunology, a short course. 11. Cytokine, pp , 6th ed., John Wiley & sons, Inc., : Hoboken NJ, USA. 7. Cox, D. A. and Bürk. R. R Isolation and characterization of milk growth factor, a transforming-growthfactor-β2-related polypeptide, from bovine milk. Eur. J. Biochem. 197: Eckert, R. L., Efimova, T., Dashti, S. R., Balasubramanian, S., Deucher, A., Crish, J. F., Stutniolo, M. and Bone, F Keratinocyte survival, differenentiation, and death: many roads lead to mitogen-activated protein kinase. J. Invest. Dermatol. Symp. Proc. 7: Efimova, T., Broome, A. M. and Eckert, R. L A regulatory role for p38 delta MAPK in keratinocyte differentiation. Evidence for p38 delta-erk1/2 complex formation. J. Biol. Chem. 278: Gaffen, S. L Recent advances in the IL_17 cytokine family. Curr. Opin. immunol. 23: Hironaka, T., Ohishi, H. and Masaki, T Identification and partial purification of a basic fibroblast growth factor-like growth factor derived from bovine colostrum. J. Dairy Sci. 80: Hwang, K. A., Yang, H. J., Ha, W. and Lee, S. W Effect of bovine colostral whey fraction containing insulinlike growth factor on cell proliferation. Kor. J. Food Sci. Ani. Resour. 24: Iacopetta, B. J., Grieu, F., Horisberger, M. and Sunahara, G. I Epidermal growth factor in human and bovine milk. Acta Paediatr. 81: Jin, Y., Cox, D. A., Knecht, R., Raschdorf, F. and Cerletti, N Separation, purification and sequence identification of TGF-β1 and TGF-β2 from bovine milk. J. Protein Chem. 10: Klagsburn, M Human milk stimulates DNA synthesis and cellular proliferation in cultured fibroblasts. Proc. Natl. Acad. Sci. USA 75: Klagsburn, M Bovine colostrum supports the serumfree proliferation of epithelial cells but not of fibroblasts in long-term culture. J. Cell Biol. 84: Klagsburn, M. and Neumann, J The serum-free growth of Balb/c 3T3 cells in medium supplemented with bovine colostrum. J. Supramol. Struct. 1111: Kovacs, D., Cardinali, G., Aspite, N. and Picardo, M Bovine colostrum promotes growth and migration of the human keratinocyte HaCaT cell line. Growth Factors. 27: Krstic, A., Mojsilovic, S., Jovcic, G. and Bugarski, D The potential of interleukin-17 to mediated hematopoietic response. Immunol. Res. 52: Kwon, Y. B., Choi, D. K., Sohn, K. C., Jeon, E. K., Nam, M. S., Lee, J. H. and Kim, C. D Effects of colostrum on keratinocyte differentiation and wound healing. Kor. J. Invest. Dermat. 14: Larson, L. L., Owen, F. G., Albright, J. L., Appleman, R. D., Lamb, R. C. and Muller, L. D Guidelines toward more uniformity in measuring and reporting calf experimental data. J. Dairy Sci. 60: Nam, M. S., Bae, H. C., Kim, P. H., Kim, W. S. and Goh, J. S Purification of TGF-β1 from bovine colostrum. Kor. J. Food Sci. Ani. Resour. 22: O'Driscoll, K. R., Madden, P. V., Christiansen, K. M., Viage, A., Slaga, T. J., Fabbro, D., Powell, C. T. and Weinstein, I. B Overexpression of protein kinase C beta I in a murine keratinocyte sell line produces effects on cellular growth, morphology and differentiation. Cancer Lett. 83:

7 초유에함유된성장인자와기능 : 총설 Pakkanen, R., Aalto, J Growth factors and antimicrobial factors of bovine colostrum. Int. Dairy J. 7: Pakkanen, R., Kanttinen, A., Satama, L. and Aalto, J Bovine colostrum fraction as a serum substitute for the cultivation of mouse hybridomas. Appl. Microbiol. Biotechnol. 37: Plaut, K Role of epidermal growth factor and transforming growth factors in mammary development and lactation. J. Dairy Sci. 76: Playford, R. J., Floyd, D. N., Macdonald, C. E., Calnan, D. P., Adenekan, R. O., Johson, W., Goodlad, R. A. and Marchbank, T Bovine colostrum is a health food supplement which prevents NSAID induced gut damage. Gut. 44: Playford, R., Macdonald, C. E. and Johnson, W. S Colostrum and milk-derived peptide growth factors for the treatment of gastrointestinal disorders. Am. J. Clin. Nutr. 72: Purup, S., Vestergaard, M., Pedersen, L. O. and Sejrsen, K Biological activity of bovine milk on proliferation of human intestinal cells. J. Dairy Res. 74: Rathe, M., Müller, K., Sangild, P. T. and Husby, S Clinical applications of bovine colostrum therapy: a systematic review. Nutrition Reviews 72: Read, I. C., Francis, G. I., Wallace, J. C. and Ballard, F. J Growth factor concentration and growth promoting activity in human milk following premature birth. J. Dev. Physiol. 7: Sacerdote, P., Mussano, F., Franchi, S., Panerai, A. E., Bussolati, G., Carossa, S., Bartorelli, A. and Bussolati, B Biological componentsin a standardized derivative of bovine colostrum. J. Dairy Sci. 96: Torre, C., Jeusette, I., Serra, M., Brazis, P. and Puigdemont, A Bovine colostrum increases proliferation of canine skin fibroblasts. J. Nutr. 136:2058S-2060S. Received 20 January, 2016 Revised 20 February, 2016 Accepted 28 February, 2016

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