White Paper: Chemokines as Biomarkers

Printer_Friendly

 

Introduction

Chemokines have been defined as small cytokines involved in the migration and activation of cells such as lymphocytes and phagocytic cells, playing a central role in inflammation [1]. The term itself is a combination of chemotaxis and cytokine. Chemokines work through a large family of G protein coupled receptors. Chemokines are classified in families (CXC, C, CX3C, and CC) with the ligands named with an L and the receptors named with an R. For example IL-8 is classified as CXCL8 and its receptors are CXCR1 and CXCR2 [2]. However many chemokines are still known by their traditional names. In addition to inflammation, chemokines are major regulators of malignancy and are produced by tumor cells[3]. All cells are likely able to produce chemokines under certain conditions. Chemokines are redundant in their action on target cells and chemokine/receptor interactions are promiscuous with receptors interacting with multiple ligands [4]. Chemokines are present in the human plasma proteome at higher concentrations than cytokines [5] making them easier to detect and quantify using ELISA and mass spectroscopy techniques. Because of the widespread production, the stability and long half life of the proteins [6],and the higher concentrations at which they can be found, chemokines are being considered as biomarkers of various diseases. Serum CCL11 or eotaxin-1 has been shown to be present at concentrations in the hundreds of pg/ml [7] has been put forward as a biomarker for prostate cancer [8]. The interferon regulated chemokines have been shown to be effective as serum biomarkers in measuring the progression and activity in systemic lupus erythematosus. [9]. Urinary chemokines look promising as biomarkers of kidney damage such as lupus nephritis [10] and urinary Gro-α (CXCL1) looks promising as an early biomarker of renal ischemia/reperfusion [11]. Chemokines have also been examined as biomarkers of cardiovascular risk [12] with additional studies recommended to work out issues with sample collection and treatment as well as prospective studies [6]. Below is a brief discussion of the functions and roles of a few important cytokines as potential biomarkers of disease.

Eotaxin (CCL11)

Eotaxin is an eosinophil selective chemotractant with minimal effect on other leukocytes and its activity in vivo is elevated by the presence of IL-5[13]. It exerts its activity through the CCR-3. While CCR-3 is promiscuous, being activated by regulated on activation, normal T-cell expressed and secreted (RANTES) and MCP-2-4, eotaxin is the only chemokine to exclusively use CCR-3 [13]. Serum eotaxin (CCL11) along with interferon inducible protein-10 (IP-10) have been advanced as early biomarkers of age related macular degeneration [14],Eotaxin is consituitively expressed in the gut . In the airway eotaxin mRNA has been found to be produced in as little as 60 min following exposure of TNF-α, IL-1, or interferon gamma. Eosinophils constituitively express eotaxin wich may lead to autoamplifications of eosinophil recruitment into inflammatory sites. [13] Eotaxin also induces respiratory burst or the production of reactive oxygen species in eosinophils via phosphoinositide-3 (PI3K), protein kinase C (PKC) and tyrosine kinases via inhibition studies [15] Eotaxin promotes the release of the anti-inflammatory cytokine IL-4 from eosinophils in a non-cytolytic manner that is enhanced by IL-5, but inhibited by brefeldin A an inhibitor of vesicle formation. It has been hypothesized that one of the mechanisms of glucocorticoid inhibition is through eotaxin suppression [15]. Eotaxin activity is controlled by cleavage and degradation by the membrane associated serine protease CD26 [15]. Elevated plasma eotaxin levels have been observed in subjects with liver cirrhosis and has been put forward as a biomarker for aging and cancer [16] as well as a biomarker indicating adverse prognosis in chronic liver disease [17]. Eotaxin ranges in that study were from 8.3-1578 and averaged 47.8 pg/ml in 111 patients with chronic liver disease[17].

GRO-α (CXCL1)

Originally thought to be a melanoma growth stimulatory factor and labeled melanoma growth stimulatory activity Gro-α is a chemokine that is structurally similar to interleukin (IL)-8 and is an activator of neutrophils inducing, chemotaxis, excytosis, and respiratory burst [18]. Gro-α has been shown to be upregulated following administration of IL-2 to patients with renal cell cancer [19] and high concentrations of Gro-α predict radiographic progression in rheumatoid arthritis patients taking methotrexate [20]. As Gro-α is tumorgenic on nude mice as well as exhibiting the aforementioned stimulation of melanoma, it has been labled as “the most striking evidence of the direct regulation of tumors and tumor growth by chemokines [21].” Gro-α is also commonly known as keratinocyte derived chemokines orKC.

I-309 (CCL1)

I-309 is a monocyte chemotractant protein that exerts potent anti-apoptotic activity [22]. It appears to be metastatic and has been shown to be significantly elevated in metastasis derived cell lines [23]. I-309, in conjunction with other proteins, has promise as a cerebrospinal fluid biomarker of Alzheimer’s disease progression and cognitive impairment; [24]. CCL1 may also be a biomarker of cardiovascular risk [25].

IL-8 (CXCL8)

IL-8 is a widely studied proinflammatory chemokine that is upgreulated by NF-κB signaling and exerts its effects via the cell surface receptors CXCR1 and CXCR2 [26]. Neutrophils appear to be major targets of IL-8 signaling. IL-8 has shown to be a promising biomarker for urinry bladder cancer, prostatiti, pylenonephritis, vesicoureteral reflux, osteomyelitis, inflammatory bowel disease, chorioamnionitis, non-Hodgkin’s lymphoma, and pulmonary and nasocomial infection [27]. IL-8 may also be an effective biomarker for acute kidney injury after liver transplant surgery [28], squamous cells carcinomas of the mouth [29], and intrathecal inflammation [30]. As IL-8 appears to be a potential biomarker in multiple diseases that are seemingly only related by the inflammatory process IL-8 exhibits a lack of specificity as a biomarker pertaining to individual diseases. However, by multiplexing IL-8 with other disease associated biomarkers and performing network analysis [31] the presence of IL-8 can become a powerful biomarker for disease determination.

IP-10 (CXCL10)

Known as the interferon-γ inducible protein 10 or CXCL10, IP-10 is secreted by fibroblast, monocytes, ans endothelial cells that have been stimulate by interferon-γ and it interacts with the CXCR3 receptor. IP-10 has been shown to down-regulate angiogenesis and promote T-cell migration to inflammatory sites. It has been put forward as a serum biomarker of systemic lupus erythematosis and lupus nephritis as there have been observations of increases in serum concentrations of IP-10 in patients diagnosed with the diseases [32]. IP-10 is a promising biomarker for Mycobacterium tuberculosis infection [33] as well as for asthma [34] and COPD [35] exacerbation following rhinovirus infection. CXCL10 is a potential biomarker for sepsis [36], severity of liver disease [37], as serum biomarker of viral infection [38].

MCP-1 (CCL2)

Monocyte chemotactic protein (MCP-1 or CCL2) is a widely studied chemokine that is very potent in its ability to mobilize monocytes. Like many chemokines it is produced by multiple cell types such as smooth muscle, mesangial, astrocytic, microglial, fibroblasts, and epithelial, cells although the major producers of MCP-1 appear to be monocytes/macrophages. CCL2 is also thought to be an intervention point for treatment of many diseases [39]. MCP-1 has not only been shown to stimulate IL-4 production and attract monocytes to the site of inflammation contributing to their maturity into macrophages, it has been shown to be correlated with viral load in HIV infection [39]. It may have some antitumor activity [39] but it is also considered a pivotal mediator in the pathogenesis of atherosclerosis[40]. Urinary MCP-1 may be useful as a biomarker of SLE activity [41] while plasma MCP-1 has been postulated to be a marker of cardiac aging [42].

MCP-2 (CCL8)

MCP-2, like MCP-1, MCP-3 and MCP-4 binds to the CCR2 receptor [43]. Like MCP-1, MCP 2 has been found in multiple sclerosis brain lesions [44]. MCP-2 can be differentiated from MCP-1 in that MCP-2 stimulates eosinophils and basophils while MCP-1 activates only basophils [45]. In conjunction with IP-10, MCP-2 appears to be a biomarker for tuberculosis diagnosis [46] and possibly SLE [47] and rheumatoid arthritis [48].

RANTES (CCL5)

RANTES like MCP-1 attracts monocytes, and target memory T cells, (via different receptors) RANTES also triggers chemotaxis and activation of eosinophils [39]. It appears to be an effective biomarker in differentiating infection from types of pneumonia [49] as well as other viral infections [50] and cardiac mortality [51].

TARC (CCL17)

Thymus and activation related chemokine (TARC) is produced by dendritic and other antigen presenting cells and attracts T cells via the CCR4. TARC appears to be a good marker for monitoring treatment and disease progression in patients with Hodgkin’s disease [52]. It is a postulated target of therapeutics for allergies [53] and potential biomarker for atopic dermatitis [54]. It has also been investigated as a biomarker in diverse illness such as malaria [55], Gaucher’s [56], and cancer [57].

Conclusion

While the characteristics of chemokines that make them easy to detect and quantify also limit the specificity of individual chemokines as biomarkers. As with many protein biomarkers, multiplexing appears superior to single protein[58]. It would likely be advantageous to consider examining alterations in chemokine concentrations in your research as well. The Quansys Human Chemokine array contains ELISAs for Eotaxin, GROa, I-309, IL-8, IP-10, MCP-1, MCP-2, RANTES, TARC which will allow you to measure alterations in the concentrations of the above mentioned chemokines. Also the chemokines can be readily combined with other cytokines such as interleukins for a low cost custom Q-Plex ELISA array delivered to you with minimal turnaround time.

References

  1. Janeway, C. and P. Travers, Immunobiology: the immune system in health and disease. 1994, New York: Current Biology Limited Garland Pub. Inc. 1 v. (various pagings).
  2. Bacon, K., et al., Chemokine/chemokine receptor nomenclature. J Leukoc Biol, 2001. 70(3): p. 465-6.
  3. Handel, T.M. and D.J. Hamel, Chemokines. 1st ed. 2009, Amsterdam ; Boston: Elsevier/Academic Press. v. <1-2 >.
  4. Mantovani, A., Chemokines. Chemical immunology; v.72. 1999, Basel ; New York: Karger. xi, 208 p.
  5. Anderson, N.L. and N.G. Anderson, The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics, 2002. 1(11): p. 845-67.
  6. Aukrust, P., et al., Chemokines and cardiovascular risk. Arterioscler Thromb Vasc Biol, 2008. 28(11): p. 1909-19.
  7. Syversen, S.W., et al., A high serum level of eotaxin (CCL 11) is associated with less radiographic progression in early rheumatoid arthritis patients. Arthritis Res Ther, 2008. 10(2): p. R28.
  8. Agarwal, M., et al., CCL11 (eotaxin-1): A new diagnostic serum marker for prostate cancer. Prostate, 2012.
  9. Bauer, J.W., et al., Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum, 2009. 60(10): p. 3098-107.
  10. Ferri, G.M., et al., Urine chemokines: biomarkers of human lupus nephritis? Eur Rev Med Pharmacol Sci, 2007. 11(3): p. 171-8.
  11. Molls, R.R., et al., Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol, 2006. 290(5): p. F1187-93.
  12. Aukrust, P., et al., Chemokines in cardiovascular risk prediction. Thromb Haemost, 2007. 97(5): p. 748-54.
  13. Rothenberg, M.E., Eotaxin. An essential mediator of eosinophil trafficking into mucosal tissues. Am J Respir Cell Mol Biol, 1999. 21(3): p. 291-5.
  14. Mo, F.M., et al., Interferon gamma-inducible protein-10 (IP-10) and eotaxin as biomarkers in age-related macular degeneration. Invest Ophthalmol Vis Sci, 2010. 51(8): p. 4226-36.
  15. Bandeira-Melo, C., A. Herbst, and P.F. Weller, Eotaxins. Contributing to the diversity of eosinophil recruitment and activation. Am J Respir Cell Mol Biol, 2001. 24(6): p. 653-7.
  16. Fimmel, S., et al., GRO-alpha: a potential marker for cancer and aging silenced by RNA interference. Ann N Y Acad Sci, 2007. 1119: p. 176-89.
  17. Tacke, F., et al., Up-regulated eotaxin plasma levels in chronic liver disease patients indicate hepatic inflammation, advanced fibrosis and adverse clinical course. J Gastroenterol Hepatol, 2007. 22(8): p. 1256-64.
  18. Geiser, T., et al., The interleukin-8-related chemotactic cytokines GRO alpha, GRO beta, and GRO gamma activate human neutrophil and basophil leukocytes. J Biol Chem, 1993. 268(21): p. 15419-24.
  19. Panelli, M.C., et al., Forecasting the cytokine storm following systemic interleukin (IL)-2 administration. J Transl Med, 2004. 2(1): p. 17.
  20. Davis, J.M. and E.L. Matteson, Cytokine biomarkers and the promise of personalized therapy in rheumatoid arthritis. Reumatología Clínica, 2009. 05(04): p. 143-146.
  21. Huang, F. and X.P. Geng, Chemokines and hepatocellular carcinoma. World J Gastroenterol, 2010. 16(15): p. 1832-6.
  22. Denis, C., et al., C-terminal clipping of chemokine CCL1/I-309 enhances CCR8-mediated intracellular calcium release and anti-apoptotic activity. PLoS One, 2012. 7(3): p. e34199.
  23. Abajo, A., et al., Identification of colorectal cancer metastasis markers by an angiogenesis-related cytokine-antibody array. World J Gastroenterol, 2012. 18(7): p. 637-45.
  24. Hu, W.T., et al., Novel CSF biomarkers for Alzheimer’s disease and mild cognitive impairment. Acta Neuropathol, 2010. 119(6): p. 669-78.
  25. Wykrzykowska, J.J., et al., Differential protein biomarker expression and their time-course in patients with a spectrum of stable and unstable coronary syndromes in the Integrated Biomarker and Imaging Study-1 (IBIS-1). Int J Cardiol, 2011. 149(1): p. 10-6.
  26. Waugh, D.J. and C. Wilson, The interleukin-8 pathway in cancer. Clin Cancer Res, 2008. 14(21): p. 6735-41.
  27. Shahzad, A., et al., Interleukin 8 (IL-8) – a universal biomarker? Int Arch Med, 2010. 3: p. 11.
  28. Sirota, J.C., et al., Urine IL-18, NGAL, IL-8 and serum IL-8 are biomarkers of acute kidney injury following liver transplantation. BMC Nephrol, 2013. 14: p. 17.
  29. St. John, M.R., et al., Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Archives of Otolaryngology—Head & Neck Surgery, 2004. 130(8): p. 929-935.
  30. Bielekova, B., et al., Cerebrospinal fluid IL-12p40, CXCL13 and IL-8 as a combinatorial biomarker of active intrathecal inflammation. PLoS One, 2012. 7(11): p. e48370.
  31. Broderick, G., et al., Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue. J Transl Med, 2012. 10: p. 191.
  32. Reyes-Thomas, J., I. Blanco, and C. Putterman, Urinary biomarkers in lupus nephritis. Clin Rev Allergy Immunol, 2011. 40(3): p. 138-50.
  33. Strzelak, A., A. Komorowska-Piotrowska, and J. Ziolkowski, [CXCL10/IP-10 as a new biomarker for Mycobacterium tuberculosis infection]. Pol Merkur Lekarski, 2012. 33(198): p. 342-5.
  34. Quint, J.K., IP-10 as a biomarker for rhinoviral infections in asthma. Thorax, 2008. 63(3): p. 200.
  35. Quint, J.K., et al., Serum ip-10 as a biomarker of human rhinovirus infection at exacerbation of copd. CHEST Journal, 2010. 137(4): p. 812-822.
  36. Pierrakos, C. and J.L. Vincent, Sepsis biomarkers: a review. Crit Care, 2010. 14(1): p. R15.
  37. Sultana, C., et al., Predictors of Chronic Hepatitis C Evolution in HIV Co-Infected Patients From Romania. Hepat Mon, 2013. 13(2): p. e8611.
  38. Chan, T. and F. Gu, Early diagnosis of sepsis using serum biomarkers. Expert Rev Mol Diagn, 2011. 11(5): p. 487-96.
  39. Deshmane, S.L., et al., Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res, 2009. 29(6): p. 313-26.
  40. Gonzalez-Quesada, C. and N.G. Frangogiannis, Monocyte chemoattractant protein-1/CCL2 as a biomarker in acute coronary syndromes. Curr Atheroscler Rep, 2009. 11(2): p. 131-8.
  41. Barbado, J., et al., MCP-1 in urine as biomarker of disease activity in Systemic Lupus Erythematosus. Cytokine, 2012. 60(2): p. 583-586.
  42. Chiao, Y.A., et al., Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging. Circ Cardiovasc Genet, 2011. 4(4): p. 455-62.
  43. Ota, T., Chemokine systems link obesity to insulin resistance. Diabetes Metab J, 2013. 37(3): p. 165-72.
  44. McManus, C., et al., MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study. Journal of Neuroimmunology, 1998. 86(1): p. 20-29.
  45. Proost, P., A. Wuyts, and J. Van Damme, Human monocyte chemotactic proteins-2 and -3: structural and functional comparison with MCP-1. J Leukoc Biol, 1996. 59(1): p. 67-74.
  46. Ruhwald, M., et al., Evaluating the potential of IP-10 and MCP-2 as biomarkers for the diagnosis of tuberculosis. Eur Respir J, 2008. 32(6): p. 1607-15.
  47. Bauer, J.W., et al., Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med, 2006. 3(12): p. e491.
  48. Rioja, I., et al., Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor α, tumor necrosis factor receptor superfamily member 9, and macrophage colony-stimulating factor. Arthritis & Rheumatism, 2008. 58(8): p. 2257-2267.
  49. Miyazaki, E., et al., Circulating thymus- and activation-regulated chemokine/ccl17 is a useful biomarker for discriminating acute eosinophilic pneumonia from other causes of acute lung injury*. CHEST Journal, 2007. 131(6): p. 1726-1734.
  50. Ng, L.F., et al., IL-1beta, IL-6, and RANTES as biomarkers of Chikungunya severity. PLoS One, 2009. 4(1): p. e4261.
  51. Cavusoglu, E., et al., Low plasma RANTES levels are an independent predictor of cardiac mortality in patients referred for coronary angiography. Arterioscler Thromb Vasc Biol, 2007. 27(4): p. 929-35.
  52. Weihrauch, M.R., et al., Elevated serum levels of CC thymus and activation-related chemokine (TARC) in primary Hodgkin’s disease: potential for a prognostic factor. Cancer Res, 2005. 65(13): p. 5516-9.
  53. Ferreira, M.A.R., Cytokine expression in allergic inflammation: systematic review of in vivo challenge studies. Mediators of Inflammation, 2003. 12(5): p. 259-267.
  54. Saeki, H. and K. Tamaki, Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases. J Dermatol Sci, 2006. 43(2): p. 75-84.
  55. Armah, H., et al., Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children. Malaria Journal, 2007. 6(1): p. 147.
  56. Pavlova, E.V., et al., Potential biomarkers of osteonecrosis in Gaucher disease. Blood Cells, Molecules, and Diseases, 2011. 46(1): p. 27-33.
  57. Duell, E.J., et al., Inflammation, Genetic Polymorphisms in Proinflammatory Genes TNF-A, RANTES, and CCR5, and Risk of Pancreatic Adenocarcinoma. Cancer Epidemiology Biomarkers & Prevention, 2006. 15(4): p. 726-731.
  58. Olson, L. and C. Humpel, Growth factors and cytokines/chemokines as surrogate biomarkers in cerebrospinal fluid and blood for diagnosing Alzheimer’s disease and mild cognitive impairment. Exp Gerontol, 2010. 45(1): p. 41-6.

About Us

"We are dedicated to the development of protein arrays that aid researchers and clinicians in better understanding, diagnosing, and treating disease. Our products and services provide value to customers by improving the accuracy and efficiency of their testing."

Quality

Quansys Biosciences is an ISO 9001 and ISO 13485 registered company. We pride ourselves in the quality of our product and our commitment to customer satisfaction.


Quansys Bioscience
Fax: 435-750-6869
888-QUANSYS (782-6797)