ABB  Vol.4 No.7 A , July 2013
Cytokine profiles in sickle cell anemia: Pathways to be unraveled
ABSTRACT
Sickle cell anemia (SCA) is a genetically inherited hemolytic disorder characterized by chronic inflammation. Cytokine expression affects the pivotal pathways that contribute to disease pathogenesis, but the mechanisms involved are not well understood. SCA is associated with a proinflammatory state, and an enhanced inflammatory response occurs during vasoocclusive crisis. The immune system thus plays an important role in this inflammatory condition, with several cell types secreting pro-inflammatory cytokines that contribute to the occurrence of common cyclical events in SCA patients, such as hemolysis, vascular occlusion and inflammation. Studies of these cytokines and chemokines in SCA patients have clarified the mechanisms that underlie this disease and highlighted the need for a better understanding of cytokine participation in SCA pathophysiology.

Cite this paper
Pitanga, T. , Vilas-Boas, W. , Cerqueira, B. , Seixas, M. , Barbosa, C. , Adorno, E. and Goncalves, M. (2013) Cytokine profiles in sickle cell anemia: Pathways to be unraveled. Advances in Bioscience and Biotechnology, 4, 6-12. doi: 10.4236/abb.2013.47A1002.
References
[1]   Steinberg, M.H. and Rodgers, G.P. (2001) Pathophysiology of sickle cell disease: Role of cellular and genetic modifiers. Seminars in Hematology, 38, 299-306. doi:10.1016/S0037-1963(01)90023-X

[2]   Rother, R.P., Bell, L., Hillmen, P. and Gladwin, M.T. (2005) The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: A novel mechanism of human disease. JAMA, 293, 1653-1662. doi:10.1001/jama.293.13.1653

[3]   Frenette, P.S. (2002) Sickle cell vaso-occlusion: Multistep and multicellular paradigm. Current Opinion Hematology, 9, 101-106. doi:10.1097/00062752-200203000-00003

[4]   Levy, D.E. and Darnell Jr., J.E. (2002) Stats: Transcriptional control and biological impact. Nature Reviews. Molecular Cell Biology, 3, 651-662. doi:10.1038/nrm909

[5]   Martinon, F., Mayor, A. and Tschopp, J. (2009) The inflammasomes: Guardians of the body. Annual Review of Immunology, 27, 229-265. doi:10.1146/annurev.immunol.021908.132715

[6]   Matzinger, P. (1994) Tolerance, danger, and the extended family. Annual Review of Immunology, 12, 991-1045. doi:10.1146/annurev.iy.12.040194.005015

[7]   Kono, H. and Rock, K.L. (2008) How dying cells alert the immune system to danger. Nature Reviews Immunology, 8, 279-289. doi:10.1038/nri2215

[8]   Shi, Y., Evans, J.E. and Rock, K.L. (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature, 425, 516-521. doi:10.1038/nature01991

[9]   Halle, A., Hornung, V., Petzold, G.C., Stewart, C.R., Monks, B.G., Reinheckel, T., Fitzgerald, K.A., Latz, E., Moore, K.J. and Golenbock, D.T. (2008) The Nalp3 inflammasome is involved in the innate immune response to amyloid-beta. Nature Immunology, 9, 857-865. doi:10.1038/ni.1636

[10]   Martinon, F., Burns, K. and Tschopp, J. (2002) The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proil-beta. Molecular Cell, 10, 417-426. doi:10.1016/S1097-2765(02)00599-3

[11]   Pathare, A., Al Kindi, S., Alnaqdy, A.A., Daar, S., KnoxMacaulay, H. and Dennison, D. (2004) Cytokine profile of sickle cell disease in Oman. American Journal of Hematology, 77, 323-328. doi:10.1002/ajh.20196

[12]   Asare, K., Gee, B.E., Stiles, J.K., Wilson, N.O., Driss, A., Quarshie, A., Adams, R.J., Kutlar, A. and Hibbert, J.M. (2010) Plasma interleukin-1beta concentration is associated with stroke in sickle cell disease. Cytokine, 49, 39-44. doi:10.1016/j.cyto.2009.10.002

[13]   Wanderer, A.A. (2009) Rationale for Il-1beta-targeted therapy to minimize hypoxic-ischemic encephalopathy. Journal of Perinatology, 29, 785-787. doi:10.1038/jp.2009.114

[14]   Cerqueira, B.A., Boas, W.V., Zanette, A.D., Reis, M.G. and Goncalves, M.S. (2011) Increased concentrations of il-18 and uric acid in sickle cell anemia: Contribution of hemolysis, endothelial activation and the inflammasome. Cytokine, 56, 471-476. doi:10.1016/j.cyto.2011.08.013

[15]   Dostert, C., Petrilli, V., Van Bruggen, R., Steele, C., Mossman, B.T. and Tschopp, J. (2008) Innate immune activation through nalp3 inflammasome sensing of asbestos and silica. Science, 320, 674-677. doi:10.1126/science.1156995

[16]   Machado, P.R.L., Araújo, M.A.S., Carvalho L. and Carvalho, E. M. (2004) Mecanismos de resposta imune às infeccoes. Anais Brasileiro de Dermatologia, 79, 647-662. doi:10.1590/S0365-05962004000600002

[17]   Frenette P.S. (2004) Sickle cell vaso-occlusion: Heterotypic, multicellular aggregations driven by leukocyte adhesion. Microcirculation, 11, 167-177.

[18]   Janeway, C.A., Travers, P., Walport, M. and Shlomchik, M. (2001) Immunobiology. 5th Edition, Garland Publishing, New York, 90-100.

[19]   Heinrich, P.C., Behrmann, I., Haan, S., Hermanns. H.M., Müller-Newen, G. and Schaper, F. (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemistry Journal, 374, 1-20. doi:10.1042/BJ20030407

[20]   Mansell, A. and Jenkins, B.J. (2013) Dangerous liaisons between interleukin-6 cytokine and toll-like receptor families: A potent combination in inflammation and cancer. Cytokine & Growth Factor Reviews. doi:10.1016/j.cytogfr.2013.03.007

[21]   Abbas, A.K., Lichtman, A.H. and Pober, J.S. (2000) Section III—Effector mechanisms of the immune response. Celular and Molecular Immunology.

[22]   Hibbert, J.M., Hsu, L.L., Bhathena, S.J., Irune, I., Sarfo, B., Creary, M.S., Gee, B.E., Mohamed, A.I., Buchanan, I.D., Al-Mahmoud, A. and Stiles, J.K. (2005) Proinflammatory cytokines and the hypermetabolism of children with sickle cell disease. Experimental Biology and Medicine, 230, 68-74.

[23]   Veiga, P.C., Schroth, R.J., Guedes, R., Freire, S.M. and Nogueira-Filho, G. (2013) Serum cytokine profile among Brazilian children of African descent with periodontal inflammation and sickle cell anaemia. Archives Oral Biology, 58, 505-510. doi:10.1016/j.archoralbio.2012.11.006

[24]   Walter, P.B., Fung, E.B., Killilea, D.W., Jiang, Q., Hudes, M., Madden, J., Porter, J., Evans, P., Vichinsky, E. and Harmatz, P. (2006) Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. British Journal of Haematology, 135, 254-263. doi:10.1111/j.1365-2141.2006.06277.x

[25]   Qari, M.H., Dier, U. and Mousa, S.A. (2012) Biomarkers of inflammation, growth factor, and coagulation activation in patients with sickle cell disease. Clinical and Applied Thrombosis Hemostasis, 18, 195-200. doi:10.1177/1076029611420992

[26]   Li, A., Varney, M.L., Valasek, J., Godfrey, M., Dave, B.J. and Singh, R.K. (2005) Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis, 8, 63-71. doi:10.1007/s10456-005-5208-4

[27]   Ikram, N., Hassan, K. and Tufail, S. (2004) Cytokines. International Journal of Pathology, 2, 47-58.

[28]   Graves, D.T. and Jiang, Y. (1995) Chemokines, a family of chemotactic cytokines. Critical Reviews in Oral Biology and Medicine, 6, 109-118. doi:10.1177/10454411950060020101

[29]   Wolf, M., Delgado, M.B., Jones, S.A., Dewald, B., ClarkLewis, I. and Baggiolini, M. (1998) Granulocyte chemotactic protein 2 acts via both IL-8 receptors, CXCR1 and CXCR2. European Journal of Immunology, 28, 164-170. doi:10.1002/(SICI)1521-4141(199801)28:01<164::AID-IMMU164>3.0.CO;2-S

[30]   Popa, C., Netea, M.G., van Riel, P.L., van der Meer, J.W. and Stalenhoef, A.F. (2007) The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. Journal of Lipid Research, 48, 751-762. doi:10.1194/jlr.R600021-JLR200

[31]   Keikhaei, B., Mohseni, A.R., Norouzirad, R., Alinejadi, M., Ghanbari, S., Shiravi, F. and Solgi, G. (2013) Altered levels of pro-inflammatory cytokines in sickle cell disease patients during vaso-occlusive crises and the steady state condition. European Cytokine Network.

[32]   Cajado, C., Cerqueira, B.A., Couto, F.D., Moura-Neto, J.P., Vilas-Boas, W., Dorea, M.J., Lyra, I.M., Barbosa, C.G., Reis, M.G. and Goncalves, M.S. (2011) TNF-alpha and IL-8: Serum levels and gene polymorphisms (-308G >A and -251A>T) are associated with classical biomarkers and medical history in children with sickle cell anemia. Cytokine, 56, 312-317. doi:10.1016/j.cyto.2011.07.002

[33]   Goncalves, M.S., Queiroz, I.L., Cardoso, S.A., Zanetti, A., Strapazoni, A.C., Adorno, E., Albuquerque, A., Sant’Ana, A., dos Reis, M.G., Barral, A. and Barral Netto, M. (2001) Interleukin 8 as a vaso-occlusive marker in Brazilian patients with sickle cell disease. Brazilian Journal of Medical and Biology Research, 34, 1309-1313.

[34]   Lanaro, C., Franco-Penteado, C.F., Albuqueque, D.M., Saad, S.T., Conran, N. and Costa, F.F. (2009) Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy. Journal of Leukocyte Biology, 85, 235-242. doi:10.1189/jlb.0708445

[35]   Michaels, L.A., Ohene-Frempog, K., Zhao, H. and Douglas, S.D. (1998) Serum levels of substance P are elevated in patients with sickle cell disease and increase further during vaso-occlusive crisis. Blood, 92, 3148-3151.

[36]   Tavakkoli, F., Nahavandi, M., Wyche, M.Q. and Perlin, E. (2004) Plasma levels of TNF-alpha in sickle cell patients receiving hydroxyurea. Hematology, 9, 61-64. doi:10.1080/1024533032000158869

[37]   Kim, K.S., Rajagopal, V., Gonsalves, C., Johnson, C. and Kalra, V.K. (2006) A novel role of hypoxia-inducible factor in cobalt chlorideand hypoxia-mediated expression of IL-8 chemokine in human endothelial cells. Journal Immunology, 177, 7211-7224.

[38]   Saleh, A.W., Hillen, H.F. and Duits, A.J. (1999) Levels of endothelial, neutrophil and platelet-specific factors in sickle cell anemia patients during hydroxyurea therapy. Acta Haematologica, 102, 31-37. doi:10.1159/000040964

[39]   Musa, B.O., Onyemelukwe, G.C., Hambolu, J.O., Mamman, A.I. and Isa, A.H. (2010) Pattern of serum cytokine expression and T-cell subsets in sickle cell disease patients in vaso-occlusive crisis. Clinical and Vaccine Immunology, 17, 602-608.

[40]   Kolls J.K. and Linden, A. (2004) Interleukin-17 family members and inflammation. Immunity, 21, 467-476. doi:10.1016/j.immuni.2004.08.018

[41]   Harrington, L.E., Hatton, R.D., Mangan, P.R., Turner, H., Murphy, T.L., Murphy, K.M. and Weaver, C.T. (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunology, 6, 1123-1132. doi:10.1038/ni1254

[42]   Iwakura, Y., Nakae, S., Saijo, S. and Ishigame, H. (2008) The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunological Review, 226, 57-79.

[43]   Stockinger, B. and Veldhoen, M. (2007) Differentiation and function of Th17 cells. Current Opinion in Immunology, 19, 281-286. doi:10.1016/j.coi.2007.04.005

[44]   Vilas-Boas, W., Cerqueira, B.A., Zanette, A.M., Reis, M.G., Barral-Netto, M. and Goncalves M.S. (2010) Arginase levels and their association with Th17-related cytokines, soluble adhesion molecules (sICAM-1 and sVCAM-1) and hemolysis markers among steady-state sickle cell anemia patients. Annals of Hematolology, 89, 877-882. doi:10.1007/s00277-010-0954-9

[45]   O’Shea, J.J and Paul W.E. (2002) Regulation of T(H)1 differentiation-controlling the controllers. Nature Immunology, 3, 506-508. doi:10.1038/ni0602-506

[46]   Hunter, C.A. (2005) New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nature Reviews Immunology, 5, 521-531. doi:10.1038/nri1648

[47]   Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L. and Kuchroo, V.K. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 andregulatory T cells. Nature, 11, 235-238. doi:10.1038/nature04753

[48]   Vignali, D.A. and Kuchroo, V.K. (2012) IL-12 family cytokines: Immunological playmakers. Nature Immunology, 13, 722-728. doi:10.1038/ni.2366

[49]   Taylor, S.C., Shacks, S.J. and Qu, Z. (1999) In vivo production of type 1 cytokines in healthy sickle cell disease patients. Journal of the National Medical Association, 91, 619-624.

[50]   Hassan, D.A., Marques, C., Santos-Gomes, G.M., do Rosario, V.E., Mohamed H.S., Elhussein, A.M., Ibrahim, M.E. and Abdulhadi, N.H. (2009) Differential expression of cytokine genes among sickle-cell-trait (HbAS) and normal (HbAA) children infected with Plasmodium falciparum. Annals of Tropical Medicine and Parasitology, 103, 283-295. doi:10.1179/136485909X435049

[51]   Taylor, SC., Shacks, S.J., Qu, Z. and Wiley, P. (1997) Type 2 cytokine serum levels in healthy sickle cell disease patients. Journal of the National Medical Association, 89, 753-757.

[52]   Oh, C.K., Geba, G.P. and Molfino, N. (2010) Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma. European Respiratory Review, 115, 46-54. doi:10.1183/09059180.00007609

[53]   Luzina, I.G., Keegan, A.D., Heller, N.M., Rook, G.A., Shea-Donohue, T. and Atamas, S.P. (2012) Regulation of inflammation by interleukin-4: A review of “alternatives”. Journal of Leukocyte Biology, 92, 753-764. doi:10.1189/jlb.0412214

[54]   Raghupathy, R., Haider, M.Z., Azizieh, F., Abdelsalam, R., D’Souza, T.M. and Adekile, A.D. (2000) Th1 and Th2 cytokine profiles in sickle cell disease. Acta Haematologica, 103, 197-202. doi:10.1159/000041049

[55]   Knight-Madden, J., Vergani, D., Patey, R., Sylvester, K., Hussain, M.J., Forrester, T. and Greenough, A. (2012) Cytokine levels and profiles in children related to sickle cell disease and asthma status. Journal of Interferon & Cytokine Research, 32, 1-5. doi:10.1089/jir.2011.0030

[56]   Moore, K.W., Vieira, P., Fiorentino, D.F., Trounstine, M.L., Khan, T.A. and Mosmann, T.R. (1990) Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science, 248, 1230-1234. doi:10.1126/science.2161559

[57]   Barbosa, M.C., Dos Santos, T.E., de Souza, G.F., de Assis, L.C., Freitas, M.V. and Goncalves, R.P. (2013) Impact of iron overload on interleukin-10 levels, biochemical parameters and oxidative stress in patients with sickle cell anemia. Revista Brasileira de Hematologia e Hemoterapia, 35, 29-34. doi:10.5581/1516-8484.20130011

 
 
Top