Test Id : CYTOP

Supplies: Sarstedt Aliquot Tube, 5 mL (T914)

Collection Container/Tube: Lavender top (EDTA)

Submission Container/Tube: Plastic vial

Specimen Volume: 0.5 mL Plasma

Collection Instructions:

1. Immediately after specimen collection, place the tube on wet ice.

2. Within 2 hours of collection, centrifuge at 4 degrees C, 1500 x g for 10 minutes and aliquot plasma into a plastic vial.

3. Freeze immediately.

Additional Information:

1. Plasma for this test cannot be shared with other tests. Submit specimen for this test in its own vial.

2. This test cannot be added onto a previously collected specimen.

3. If a refrigerated centrifuge is not available, it is acceptable to use a room temperature centrifuge, provided the sample is kept on wet ice before centrifugation and is frozen immediately afterward.

Plasma: 0.3 mL

Evaluating the etiology of infectious, autoimmune, or chronic inflammatory diseases, when used in conjunction with clinical information and other laboratory testing

Research studies in which an assessment of cytokine responses is needed

Cytokines are important mediators of cell-to-cell communication within the innate and adaptive immune systems. The expression of most cytokines is highly regulated and generally occurs in response to foreign or self-antigenic stimulation. The functions of cytokines are extremely varied, with many cytokines also displaying pleiotropic effects, depending on their cellular target. For example, tumor necrosis factor alpha (TNFa), interleukin (IL) 1 beta, and IL-6 induce expression of acute phase proteins in the liver. TNFa and IL-1 beta also lead to endothelial activation and are critical regulators of the hypothalamus, which can result in elevated body temperature. IL-6, in comparison, is a bridge to the adaptive immune response, by acting on B cells to induce proliferation.(1,2)

Innate immune cytokines also include key regulators which modulate the strength and duration of the inflammatory response. IL-10, although produced by both innate and adaptive immune cells, plays an important anti-inflammatory role in innate immunity by suppressing macrophage and dendritic cell activation. IL-18 is a pro-inflammatory cytokine produced primarily through inflammasome activation that enhances natural killer (NK) cell and CD8+ T cell activation, promotes IFNg production, and serves as a potent amplifier of type 1 immune responses.(3)

Several cytokines, including IFNg and IL-17A, are released during T cell activation and play a role in coordinating adaptive and innate immune responses. IFNg, the sole type II interferon, is produced primarily by T-helper 1 (Th1) cells, cytotoxic T cells, and NK cells.(4) It promotes macrophage activation, enhances antigen presentation, supports B cell isotype switching, and drives Th1 differentiation. IL-17A, produced primarily by Th17 cells, stimulates epithelial, endothelial, and stromal cells to produce chemokines and inflammatory mediators that recruit neutrophils and other innate immune cells, underscoring its critical role in host defense against extracellular bacteria and fungi. Soluble forms of several cytokine receptors can also be detected in the peripheral circulation, providing additional regulatory control of cytokine signaling and immune responses. For example, soluble IL-2 receptor alpha (sIL-2Ra) is produced from proteolytic cleavage of the membrane-bound receptor during T cell activation, serving as a marker of immune activation.(5,6)

Chemokines represent a specialized subset of cytokines that primarily regulate leukocyte trafficking. By establishing chemotactic gradients, chemokines direct the migration of immune cells to sites of infection, inflammation, and tissue injury. Examples include CXCL10 (CXC motif chemokine ligand 10, IP-10) which recruits activated CXCR3-expressing immune cells, CXCL8 (IL-8), which recruits neutrophils through CXCR1 and CXCR2 signaling, and CCL2/MCP-1, which attracts monocytes through CCR2 signaling.(7) Additional cytokines regulate hematopoiesis and leukocyte differentiation. For example, granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes the differentiation and activation of myeloid progenitor cells into granulocytes and monocytes/macrophages.

This panel quantifies cytokines representing several arms of the immune response and is useful for evaluating the etiology of infectious, autoimmune, and inflammatory diseases based on their concentrations in plasma.(5,8-14)

CXC MOTIF CHEMOKINE LIGAND 10:

<18 years: Not established

> or =18 years: < or =240 pg/mL

INTERLEUKIN 10:

<18 years: Not established

> or =18 years: < or =4.9 pg/mL

INTERLEUKIN 18:

<18 years: Not established

> or =18 years: < or =324 pg/mL

INTERLEUKIN 6:

<18 years: Not established

> or =18 years: < or =4.4 pg/mL

MONOCYTE CHEMOATTRACTANT PROTEIN 1:

<18 years: Not established

> or =18 years: < or =198 pg/mL

GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR:

<18 years: Not established

> or =18 years: < or =4.8 pg/mL

INTERFERON GAMMA:

<18 years: Not established

> or =18 years: < or =2.5 pg/mL

INTERLEUKIN 17 ALPHA:

<18 years: Not established

> or =18 years: <5.0 pg/mL

TUMOR NECROSIS FACTOR ALPHA:

<18 years: Not established

> or =18 years: < or =11.8 pg/mL

INTERLEUKIN 1 BETA:

<18 years: Not established

> or =18 years: <2.0 pg/mL

INTERLEUKIN 8:

<18 years: Not established

> or =18 years: < or =7.6 pg/mL

SOLUBLE INTERLEUKIN 2 RECEPTOR ALPHA:

<18 years: Not established

> or =18 years: < or =1929 pg/mL

Elevated cytokine concentrations could be consistent with the presence of infection or another inflammatory process.

Results from cytokine testing should not be used to establish or exclude a specific diagnosis.

Cytokine testing should only be used in conjunction with clinical information and other laboratory testing as part of a patient's overall assessment.

Normal concentrations of cytokines do not exclude the possibility of infection or another inflammatory condition.

Cytokine concentrations could be affected by immunomodulatory agents.

Interleukin 6 (IL-6) concentrations may be elevated in patients receiving IL-6 receptor inhibitors, such as tocilizumab, due to receptor blockade and reduced clearance of IL-6. As a result, IL-6 concentrations are not reflective of adequate tocilizumab response. Additionally, patients receiving anti-IL-6 monoclonal antibodies such as siltuximab may also exhibit interference in IL-6 measurements. For both patient cohorts, a more reliable assessment of IL-6-mediated inflammation can be obtained by measuring downstream acute-phase reactants, such as C-reactive protein.

1. Chauhan P, Nair A, Patidar A, Dandapat J, Sarkar A, Saha B. A primer on cytokines. Cytokine. 2021;145:155458. doi:10.1016/j.cyto.2021.155458

2. Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018;18(12):773-789. doi:10.1038/s41577-018-0066-7

3. Landy E, Carol H, Ring A, Canna S. Biological and clinical roles of IL-18 in inflammatory diseases. Nat Rev Rheumatol. 2024;20(1):33-47. doi:10.1038/s41584-023-01053-w

4. Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol. 2018;9:847. Published 2018 May 4. doi:10.3389/fimmu.2018.00847

5. Henter JI, Sieni E, Eriksson J, et al. Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited. Blood. 2024;144(22):2308-2318. doi:10.1182/blood.2024025077

6. Bonavia AS, Samuelsen A, Liang M, et al. Comparison of whole blood cytokine immunoassays for rapid, functional immune phenotyping in critically ill patients with sepsis. Intensive Care Med Exp. 2023;11(1):70. Published 2023 Oct 13. doi:10.1186/s40635-023-00556-w

7. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12(2):121-127. doi:10.1016/s1074-7613(00)80165-x

8. Diorio C, Shaw PA, Pequignot E, et al. Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children. Blood Adv. 2020;4(20):5174-5183. doi:10.1182/bloodadvances.2020002592

9. Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. 2022;22(2):85-96. doi:10.1038/s41577-021-00547-6

10. Arvanitis P, Tziotis A, Papadimatos S, Farmakiotis D. Pathogenesis, diagnosis, and management of cytokine release syndrome in patients with cancer: Focus on infectious disease considerations. Curr Oncol. 2025;32(4):198. Published 2025 Mar 28. doi:10.3390/curroncol32040198

11. Wang L, Lv Y, Zhou L, et al. Cytokine-based models for efficient differentiation between infection and cytokine release syndrome in patients with hematological malignancies. Exp Hematol Oncol. 2024;13(1):28. Published 2024 Mar 5. doi:10.1186/s40164-024-00495-6

12. Henter JI. Hemophagocytic lymphohistiocytosis. N Engl J Med. 2025;392(6):584-598. doi:10.1056/NEJMra2314005

13. Zeng F, Zhang H, Wang S, et al. Plasma cytokine and chemokine profiles predict efficacy and toxicity of anti-CD19 CAR-T cell therapy in large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2025;25(7):e474-e486.e8. doi:10.1016/j.clml.2025.02.009

14. Wronski M, Wesselingh R, Kazzi C, et al. Neurotoxicity associated with chimeric antigen receptor T-cell therapy. J Neuroimmunol. 2025;407:578717. doi:10.1016/j.jneuroim.2025.578717

Measurements of tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, IL-8, IL-10, IL-17A, IL-18, CXC motif chemokine ligand 10, monocyte chemoattractant protein 1, interferon gamma, granulocyte-macrophage colony-stimulating factor, and soluble IL-2 receptor alpha are performed using laboratory-developed immunoassays.(Unpublished Mayo method)

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This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

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