Monocyte chemoattractant protein 1(mcp-1)

This presentation includes the role of MCP-1 as a biomarker in various diseases.

1. MONOCYTE CHEMOATTRACTANT PROTEIN -1 (MCP-1) AS A BIOMARKER By:-Pratik K. Kamu PC/2014/209 Guided By:-Dr.D.Sujatha 1

2. Contents Definition and characteristics of biomarker What is MCP-1 Site of production of MCP-1 Methods and normal levels Mechanisms and pathways Role of MCP-1 as a biomarker in various diseases Conclusion 2 5/27/2015

3. Definition Of Biomarker Biological markers (biomarkers) have been defined as “cellular, biochemical or molecular alterations that are measurable in biological media such as human tissues, cells, or fluids.” In practice, biomarkers include tools and technologies that can aid in understanding the prediction, cause, diagnosis, progression, regression, or outcome of treatment of disease. 3 5/27/2015

4. Characteristics of an ideal biomarker Standardized High sensitivity and specificity Accurate Reproducible Easy to interpret Acceptable to patients Consistent and cost effective Have an impact on clinical/risk management 4 5/27/2015

5. MCP-1 Chemokines constitute a family of chemoattractant cytokines and are subdivided into four families on the basis of the number and spacing of the conserved cysteine residues in the N-terminus of the protein. Chemokines play a major role in selectively recruiting monocytes, neutrophils, and lymphocytes, as well as in inducing chemotaxis through the activation of GPCRs. Both CCL2 and its receptor CCR2 have been demonstrated to be induced and involved in various diseases. 5 5/27/2015

6. Chemokine receptors & their ligands Family Systematic name Human ligand Chemokine receptor C Chemokine (γ chemokine ) CCL2 CCL3 CCL5 MCP-1, MCAF MIP-1 α, LD78 α RANTES CCR2 CCR1, CCR5 CCR1, CCR5 CC Chemokine (β chemokine ) CCL13 CCL14 MCP-4 HCC-1 CCR1, CCR2, CCR3 CCR1 CXC Chemokine (α chemokine ) CXCL8 CXCL9 IL-8 MIG CXCR1, CXCR2 CXCR3-A, CXCR3-B CX3C Chemokine (δ chemokine ) CX3CL1 Fractalkine CX3CR1 6 5/27/2015

7. Structure of MCP-1 Satish L. Deshmane et al Journal of Interferon & Cytokine Research ,Volume 29, Number 6, 2009 , 315 7 5/27/2015

8. Continued 8 5/27/2015

9. Site of production of MCP-1 CCL2 is: A monomeric polypeptide, with a molecular weight of approximately 13 kDa. A nchored in the plasma membrane of endothelial cells by glycosaminoglycan side chains of proteoglycans. Primarily secreted by monocytes ,macrophages and dendritic cells. Platelet derived growth factor is a major inducer of CCL2 gene. To become activated CCL2 protein has to be cleaved by metalloproteinases i.e. MMP-12. 9 5/27/2015

10. Mechanism and pathways of monocyte recruitment CCL2 has been demonstrated to recruit monocytes into foci of active inflammation in this regard, evidence has been provided describing the involvement of prostaglandin E2 in the attraction of monocytes to the site of inflammation and their maturity into macrophages. In addition to CCL2, several other chemokines were also shown to be involved in the recruitment of monocytes. In this regard, it has been demonstrated that the stimulation of RANTES leads to recruitment monocytes. 10 5/27/2015

11. Normal levels and methods of measurement of MCP-1 Priyanka et al, International journal of diabetes mellitus 2(2010)15-19 11 5/27/2015

12. Involvement of CCL2 in different diseases Effects Mechanism References Thrombus formation By generating tissue factor Charo and Taubman 2004 Oxygen-induced injury (retinopathy) Marked increase in CCL2 in microglia/ macrophages Davies and others 2006 Inflammatory bowel disease CCL2-mediated differentiation of intestinal macrophages Spoettl and others 2006 Allergic asthma IL-4 and IL-13-induced release of CCL2 in bronchial epithelium Ip and others 2006 12 5/27/2015

13. Role of MCP-1 in diabetic nephropathy In the kidney, this can lead to the development of an innate immune response which is predominantly characterized by the accumulation of kidney macrophages . Studies in human and experimental diabetic nephropathy have shown that kidney macrophage accumulation is associated with the progression of diabetes ,the development of renal injury and kidney fibrosis and the decline in renal function, suggesting that it is an inflammatory-mediated disease 13 5/27/2015

14. Role of MCP-1 in diabetic nephropathy G. H. Tsche1,2 am J physiol renal physiol 294: F697–F701, 2008. 14 5/27/2015

15. Role of MCP-1 in cardiovascular diseases 15 5/27/2015

16. Role of MCP-1 in cardiovascular diseases Jianli niu and pappachan e. Kolattukudy clinical science (2009) 117 , 95–109 16 5/27/2015

17. R ole of MCP-1 in cancer Chemokines are involved in a broad array of normal host activities that impact cancer ; therefore, it is possible that they will be found to have important effects on cancer pathogenesis. Because of their ability to attract and activate lymphocytes, some chemokines might be expected to stimulate host antitumor responses. S ome of the chemokines are known to possess angiogenic activities, which could potentially contribute to tumor growth and progression . 17 5/27/2015

18. R ole of MCP-1 in cancer I. Conti, B.J. Rollins , Seminars in Cancer Biology 14 (2004) 149–154 18 5/27/2015

19. CCR2 Antagonists CAS 445479-97-0 RS 504393 Highly selective CCR2 chemokine receptor antagonist BMS CCR2 22 High affinity, potent CCR2 antagonist INCB 3284 dimesylate Selective CCR2 antagonist 5/27/2015 19

20. Conclusion CCL2 remains one of the most studied of the chemokines. Urinary levels of MCP-1 can be monitored as a marker of diabetic renal inflammation, and this may prove to have significant diagnostic value in assessing the effectiveness of novel or combined therapies . Drugs which block several upregulated chemokine receptors,may prove to be very effective. 20 5/27/2015

21. References Hulka BS. Overview of biological markers. In: Biological markers in epidemiology (Hulka BS, Griffith JD, Wilcosky TC, eds), pp 3–15. New York: Oxford University Press, 1990.  Naylor S. Biomarkers: current perspectives and future prospects. Expert Rev Mol Diagn 3: 525–529, 2003.  Schulte PA. A conceptual and historical framework for molecular epidemiology. In: Molecular epidemiology: principles and practices (Schulte PA, Perera FP, eds), pp 3–44. San Diego: Academic Press, 1993. Niu J. "Role of MCP-1 in Cardiovascular Disease: Molecular Mechanisms and Clinical Implications." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 22 Nov. 2014. Wen- Rong Le et al, C ancer Res October 1,2014 74:3995. Charo IF, Taubman MB. 2004. Chemokines in the pathogenesis of vascular disease. Circ Res 95:858–866. Davies MH, Eubanks JP, Powers MR. 2006. Microglia and macrophages are increased in response to ischemia-induced retinopathy in the mouse retina. Mol Vis 12:467–477. Spoettl T, Hausmann M, Herlyn M, Gunckel M, Dirmeier A, Falk W,Herfarth H, Schoelmerich J, Rogler G. 2006145:190–199. Ip WK, Wong CK, Lam CW. 2006 Clin Exp Immunol 145:162–172 . 21

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