Strong inflammatory response and Th1-polarization profile in children with acute lymphoblastic leukemia without apparent infection

Pérez-Figueroa,E.; Sánchez-Cuaxospa,M.; Martínez-Soto,K. A.; Sánchez-Zauco,N.; Medina-Sansón,A.; Jiménez-Hernández,E.; Torres-Nava,J. R.; Félix-Castro,J. M.; Gómez,A.; Ortega,E.; Maldonado-Bernal,C.

doi:10.3892/or.2016.4657

Strong inflammatory response and Th1-polarization profile in children with acute lymphoblastic leukemia without apparent infection

Authors:
- E. Pérez-Figueroa
- M. Sánchez-Cuaxospa
- K. A. Martínez-Soto
- N. Sánchez-Zauco
- A. Medina-Sansón
- E. Jiménez-Hernández
- J. R. Torres-Nava
- J. M. Félix-Castro
- A. Gómez
- E. Ortega
- C. Maldonado-Bernal
View Affiliations

Affiliations: Immunology and Proteomics Research Laboratory, Children's Hospital of Mexico Federico Gómez, Mexico, D.F., Mexico, Department of Hematology-Oncology, Children's Hospital of Mexico Federico Gómez, Mexico, D.F., Mexico, Oncology Service, Children's Hospital Moctezuma, Mexico, D.F., Mexico, Oncology Service, Highly Specialized Unit, General Hospital National Medical Center La Raza, Mexican Institute of Social Security, Mexico, D.F., Mexico, Research Unit on Infectious Diseases, Pediatric Hospital, National Medical Center XXI Century, Mexican Institute of Social Security, Mexico, D.F., Mexico, Department of Immunology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico, D.F., Mexico
Published online on: March 7, 2016 https://doi.org/10.3892/or.2016.4657
Pages: 2699-2706

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Children with acute lymphoblastic leukemia (ALL) often present fever. Febrile states are usually associated with infectious processes that generate an inflammatory response involving various molecules, including cytokines. However, an inflammatory response may also occur in the absence of infection. We hypothesized that the levels of inflammatory cytokines are increased in children with ALL without apparent infection. The serum levels of 13 cytokines in 99 patients with ALL and 48 non-oncological patients without apparent infection were measured using multiplex analyte profiling technology (Luminex®). The concentration of circulating pro-inflammatory cytokines associated with fever was similar between patients with ALL and fever at diagnosis and those without fever. The levels of tumor necrosis factor α, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and IL-10 were higher in patients with ALL vs. the control group (P<0.05). Moreover, the levels of the T helper 1 (interferon‑γ and IL-12) cytokines were higher in patients with ALL vs. the control group. Transforming growth factor β was lower in patients with ALL vs. the control group (P<0.05). The levels of IL-1β, IL-2, IL-4, IL-13, and IL-17 were similar in the two groups. Our results indicate that the circulating levels of seven of the important studied cytokines are elevated in patients with newly diagnosed ALL without apparent infection, reflecting a strong and deregulated inflammatory state in this disease, with a Th1-polarization profile.

View Figures

View References

1	Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, Dimitrova N, Jakab Z, Kaatsch P, Lacour B, et al EUROCARE Working Group: Childhood cancer survival in Europe 1999–2007: Results of EUROCARE-5 - a population-based study. Lancet Oncol. 15:35–47. 2014. View Article : Google Scholar
2	Landskron G, De la Fuente M, Thuwajit P, Thuwajit C and Hermoso MA: Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014:1491852014. View Article : Google Scholar : PubMed/NCBI
3	Chen GY and Nuñez G: Sterile inflammation: Sensing and reacting to damage. Nat Rev Immunol. 10:826–837. 2010. View Article : Google Scholar : PubMed/NCBI
4	Yang Q, Shi Y, Yang Y, Lou G and Chen Z: The sterile inflammation in the exacerbation of HBV-associated liver injury. Mediators Inflamm. 2015:5086812015. View Article : Google Scholar : PubMed/NCBI
5	Demaria S, Pikarsky E, Karin M, Coussens LM, Chen YC, El-Omar EM, Trinchieri G, Dubinett SM, Mao JT, Szabo E, et al: Cancer and inflammation: Promise for biologic therapy. J Immunother. 33:335–351. 2010. View Article : Google Scholar : PubMed/NCBI
6	Agyeman P, Kontny U, Nadal D, Leibundgut K, Niggli F, Simon A, Kronenberg A, Frei R, Escobar H, Kühne T, et al: A prospective multicenter study of microbiologically defined infections in pediatric cancer patients with fever and neutropenia: Swiss Pediatric Oncology Group 2003 fever and neutropenia study. Pediatr Infect Dis J. 33:e219–e225. 2014. View Article : Google Scholar : PubMed/NCBI
7	Khurana M, Lee B and Feusner JH: Fever at diagnosis of pediatric acute lymphoblastic leukemia: Are antibiotics really necessary? J Pediatr Hematol Oncol. 37:498–501. 2015. View Article : Google Scholar : PubMed/NCBI
8	Santolaya ME, Alvarez AM, Becker A, Cofré J, Enríquez N, O'Ryan M, Payá E, Pilorget J, Salgado C, Tordecilla J, et al: Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol. 19:3415–3421. 2001.PubMed/NCBI
9	Santolaya ME, Farfán MJ, De La Maza V, Cociña M, Santelices F, Alvarez AM, Avilés CL, Becker A, O'Ryan M, Román P, et al: Diagnosis of bacteremia in febrile neutropenic episodes in children with cancer: Microbiologic and molecular approach. Pediatr Infect Dis J. 30:957–961. 2011. View Article : Google Scholar : PubMed/NCBI
10	Barrera L, Montes-Servín E, Barrera A, Ramírez-Tirado LA, Salinas-Parra F, Bañales-Méndez JL, Sandoval-Ríos M and Arrieta Ó: Cytokine profile determined by data-mining analysis set into clusters of non-small-cell lung cancer patients according to prognosis. Ann Oncol. 26:428–435. 2015. View Article : Google Scholar
11	Mojtahedi Z, Khademi B, Erfani N, Taregh Y, Rafati Z, Malekzadeh M and Ghaderi A: Serum levels of interleukin-7 and interleukin-8 in head and neck squamous cell carcinoma. Indian J Cancer. 51:227–230. 2014. View Article : Google Scholar : PubMed/NCBI
12	Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ and Selvan SR: Interleukin 10 in the tumor microenvironment: A target for anticancer immunotherapy. Immunol Res. 51:170–182. 2011. View Article : Google Scholar : PubMed/NCBI
13	Buyukberber N, Buyukberber S, Sevinc A and Camci C: Cytokine concentrations are not predictive of bacteremia in febrile neutropenic patients. Med Oncol. 26:55–61. 2009. View Article : Google Scholar
14	Fleischhack G, Cipic D, Juettner J, Hasan C and Bode U: Procalcitonin-a sensitive inflammation marker of febrile episodes in neutropenic children with cancer. Intensive Care Med. 26(Suppl 2): S202–S211. 2000.
15	Castellheim A, Brekke OL, Espevik T, Harboe M and Mollnes TE: Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scand J Immunol. 69:479–491. 2009. View Article : Google Scholar : PubMed/NCBI
16	Dinarello CA: Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Int Rev Immunol. 16:457–499. 1998. View Article : Google Scholar : PubMed/NCBI
17	Horacek JM, Kupsa T, Vasatova M, Jebavy L and Zak P: Evaluation of serum levels of multiple cytokines and adhesion molecules in patients with newly diagnosed acute lymphoblastic leukemia using biochip array technology. Exp Oncol. 35:229–230. 2013.PubMed/NCBI
18	Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, et al: Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 458:776–779. 2009. View Article : Google Scholar : PubMed/NCBI
19	Su YC, Li SC, Wu YC, Wang LM, Chao KS and Liao HF: Resveratrol downregulates interleukin-6-stimulated sonic hedgehog signaling in human acute myeloid leukemia. Evid Based Complement Alternat Med. 2013:5474302013. View Article : Google Scholar : PubMed/NCBI
20	Abrahamsson J, Påhlman M and Mellander L: Interleukin 6, but not tumour necrosis factor-alpha, is a good predictor of severe infection in febrile neutropenic and non-neutropenic children with malignancy. Acta Paediatr. 86:1059–1064. 1997. View Article : Google Scholar : PubMed/NCBI
21	Diepold M, Noellke P, Duffner U, Kontny U and Berner R: Performance of interleukin-6 and interleukin-8 serum levels in pediatric oncology patients with neutropenia and fever for the assessment of low-risk. BMC Infect Dis. 8:282008. View Article : Google Scholar : PubMed/NCBI
22	Wu W, Jia Y, Du S, Tang H, Sun Y and Sun L: Changes of sulfur dioxide, nuclear factor-κB, and interleukin-8 levels in pediatric acute lymphoblastic leukemia with bacterial inflammation. Chin Med J (Engl). 127:4110–4113. 2014.
23	Civini S, Jin P, Ren J, Sabatino M, Castiello L, Jin J, Wang H, Zhao Y, Marincola F and Stroncek D: Leukemia cells induce changes in human bone marrow stromal cells. J Transl Med. 11:2982013. View Article : Google Scholar : PubMed/NCBI
24	Eisenkraft A, Keidan I, Bielorai B, Keller N, Toren A and Paret G: MCP-1 in the cerebrospinal fluid of children with acute lymphoblastic leukemia. Leuk Res. 30:1259–1261. 2006. View Article : Google Scholar : PubMed/NCBI
25	Bertolizio G, Stucchi R, Sahillioglu E, Somaini M, Dander E, Biondi A, Jankovic M, D'Amico G and Ingelmo PM: The effects of propofol and ketamine on the cytokine levels of children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 35:e296–e300. 2013. View Article : Google Scholar : PubMed/NCBI
26	Du S, Jia Y, Tang H, Sun Y, Wu W, Sun L, Du J, Geng B, Tang C and Jin H: Immune regulation of hydrogen sulfide in children with acute lymphoblastic leukemia. Chin Med J (Engl). 127:3695–3699. 2014.
27	Hatzistilianou M, Rekliti A, Athanassiadou F and Catriu D: Procalcitonin as an early marker of bacterial infection in neutropenic febrile children with acute lymphoblastic leukemia. Inflamm Res. 59:339–347. 2010. View Article : Google Scholar
28	Matti BF, Saleem MA and Sabir SF: Assessment of interleukin 1β serum level in different responder groups and stages of chronic myeloid leukemia patients on imatinb mesylate therapy. Indian J Hematol Blood Transfus. 30:247–252. 2014. View Article : Google Scholar : PubMed/NCBI
29	Wang S, Sun M, Gu C, Wang X, Chen D, Zhao E, Jiao X and Zheng J: Expression of CD163, interleukin-10, and interferon-gamma in oral squamous cell carcinoma: Mutual relationships and prognostic implications. Eur J Oral Sci. 122:202–209. 2014. View Article : Google Scholar : PubMed/NCBI
30	Weaver CT, Hatton RD, Mangan PR and Harrington LE: IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 25:821–852. 2007. View Article : Google Scholar : PubMed/NCBI
31	Weaver CT: Th17: The ascent of a new effector T-cell subset. Preface Eur J Immunol. 39:634–636. 2009. View Article : Google Scholar
32	Kolls JK and Lindén A: Interleukin-17 family members and inflammation. Immunity. 21:467–476. 2004. View Article : Google Scholar : PubMed/NCBI
33	Han Y, Ye A, Bi L, Wu J, Yu K and Zhang S: Th17 cells and interleukin-17 increase with poor prognosis in patients with acute myeloid leukemia. Cancer Sci. 105:933–942. 2014. View Article : Google Scholar : PubMed/NCBI
34	Zitvogel L and Kroemer G: CD103⁺ dendritic cells producing interleukin-12 in anticancer immunosurveillance. Cancer Cell. 26:591–593. 2014. View Article : Google Scholar : PubMed/NCBI
35	Lehmann D, Spanholtz J, Osl M, Tordoir M, Lipnik K, Bilban M, Schlechta B, Dolstra H and Hofer E: Ex vivo generated natural killer cells acquire typical natural killer receptors and display a cytotoxic gene expression profile similar to peripheral blood natural killer cells. Stem Cells Dev. 21:2926–2938. 2012. View Article : Google Scholar : PubMed/NCBI
36	Pegram HJ, Purdon TJ, van Leeuwen DG, Curran KJ, Giralt SA, Barker JN and Brentjens RJ: IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia. 29:415–422. 2015. View Article : Google Scholar