monocyte chemoattractant protein 1(mcp-1)

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

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Page 1: Monocyte chemoattractant protein  1(mcp-1)

MONOCYTE CHEMOATTRACTANT PROTEIN -1 (MCP-1) AS A

BIOMARKER

By:-Pratik K. Kamu PC/2014/209 Guided By:-Dr.D.Sujatha

Page 2: Monocyte chemoattractant protein  1(mcp-1)

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

Conclusion205/02/2023

Page 3: Monocyte chemoattractant protein  1(mcp-1)

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.

305/02/2023

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Characteristics of an ideal biomarkerStandardized

High sensitivity and specificity

Accurate

Reproducible

Easy to interpret

Acceptable to patients

Consistent and cost effective

Have an impact on clinical/risk management405/02/2023

Page 5: Monocyte chemoattractant protein  1(mcp-1)

MCP-1Chemokines 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.

505/02/2023

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Chemokine receptors & their ligandsFamily Systematic name Human ligand Chemokine

receptor

C Chemokine(γ chemokine)

CCL2CCL3CCL5

MCP-1, MCAFMIP-1α, LD78α

RANTES

CCR2CCR1, CCR5CCR1, CCR5

CC Chemokine(β chemokine)

CCL13CCL14

MCP-4HCC-1

CCR1, CCR2, CCR3CCR1

CXC Chemokine(α chemokine)

CXCL8CXCL9

IL-8MIG

CXCR1, CXCR2CXCR3-A, CXCR3-B

CX3C Chemokine(δ chemokine)

CX3CL1 Fractalkine CX3CR1

605/02/2023

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Structure of MCP-1

Satish L. Deshmane et al Journal of Interferon & Cytokine Research ,Volume 29, Number 6, 2009 , 315705/02/2023

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Continued

The monocyte chemoattractant protein-1(MCP-1/CCL2) is a member of the C-C chemokine family, and a potent chemotactic factor for monocytes.

MCP-1 is believed to be identical to JE , a gene whose expression is induced in mouse fibroblasts by platelet-derived growth factor.

805/02/2023

Page 9: Monocyte chemoattractant protein  1(mcp-1)

Site of production of MCP-1CCL2 is:

• A monomeric polypeptide, with a molecular weight of

approximately 13 kDa.

• Anchored 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. 905/02/2023

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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.1005/02/2023

Page 11: Monocyte chemoattractant protein  1(mcp-1)

Normal levels and methods of measurement of MCP-1

MCP-1 in serum - 125±42

pg/ml

uMcp-1/U.cr - 9.8±6.7

pg/mg

Sandwich enzyme-linked immunosorbent assay (ELISA)

& qPCR .

Priyanka et al, International journal of diabetes mellitus 2(2010)15-191105/02/2023

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Involvement of CCL2 in different diseasesEffects 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 ofintestinal macrophages

Spoettl and others 2006

Allergic asthma IL-4 and IL-13-induced release of CCL2 inbronchial epithelium

Ip and others 2006

1205/02/2023

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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

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Role of MCP-1 in diabetic nephropathy

G. H. Tsche1,2 am J physiol renal physiol 294: F697–F701, 2008. 1405/02/2023

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Role of MCP-1 in cardiovascular diseases

MCP-1 (monocyte chemotactic protein-1) plays a critical role in the development of cardiovascular diseases.

MCP-1, by its chemotactic activity, causes diapedesis of monocytes from the lumen to the sub endothelial space where they become foam cells, initiating fatty streak formation that leads to atherosclerotic plaque formation.

1505/02/2023

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Role of MCP-1 in cardiovascular diseases

Jianli niu and pappachan e. Kolattukudy clinical science (2009) 117, 95–109 1605/02/2023

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Role of MCP-1 in cancerChemokines 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.

Some of the chemokines are known to possess angiogenic

activities, which could potentially contribute to tumor growth and

progression.

1705/02/2023

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Role of MCP-1 in cancer

I. Conti, B.J. Rollins , Seminars in Cancer Biology 14 (2004) 149–154 1805/02/2023

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CCR2 Antagonists

CAS 445479-97-0RS 504393Highly selective CCR2 chemokine receptor antagonistBMS CCR2 22High affinity, potent CCR2 antagonistINCB 3284 dimesylateSelective CCR2 antagonist

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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.

2005/02/2023

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ReferencesHulka 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, Cancer 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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