Interleukin-4, Plasma

CPT: 83520
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Synonyms

  • IL-4
  • IL4

Expected Turnaround Time

4 - 7 days



Related Documents


Specimen Requirements


Specimen

Plasma


Volume

0.5 mL


Minimum Volume

0.3 mL (Note: This volume does not allow for repeat testing.)


Container

Lavender-top (EDTA) tube


Collection

Separate plasma from cells. Transfer plasma to a plastic transport tube.


Storage Instructions

Refrigerate; stable for 14 days. Stable at room temperature or frozen for 14 days. Freeze/thaw cycles x3.


Causes for Rejection

Gross hemolysis; sample left on cells


Test Details


Use

This test is used for the measurement of Interleukin-4 (IL-4) levels in plasma.


Limitations

This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.


Methodology

Enzyme-linked immunosorbent assay (ELISA)


Additional Information

Cytokines are low-molecular-weight intercellular signaling molecules that are produced de novo in response to an immune stimulus.1-3 They regulate immune cell homeostasis by mediating innate and acquired immunity and inflammation in human health and disease. They generally (although not always) act over short distances and short time spans and at very low concentrations. They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behavior. Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation and secretion of effector molecules. It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types (pleiotropy). Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. Cytokines are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines. Cytokines can also act synergistically (two or more cytokines acting together) or antagonistically (cytokines causing opposing activities).

T Helper cells (TH cells), also known as CD4+ cells or CD4-positive cells, play an important role in the adaptive immune system. They are essential in B cell antibody class switching,4,5,6 breaking cross-tolerance in dendritic cells, activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. IL-4 acts on both B and T cells. It is a B-cell growth factor and causes IgE and IgG1 isotype selection.7 It causes TH2 differentiation and proliferation, and it inhibits IFN gamma-mediated activation on macrophages. It promotes mast cell proliferation in vivo.8 Naive TH cells (T0 cells) differentiate into two major TH helper subtypes, referred to as TH1 and TH2 cells. TH2 cells produce interleukin-4 (IL-4) along with IL-5 and IL-13.2,9 Peripheral TH0 cells, upon recognition of antigenic peptides by the T cell receptor (TCR), migrate into lymphoid tissues and functionally differentiate into different TH cell subsets.10 IL-4 promotes TH2 immune response by inducing the differentiation of TH0 cells to TH2 cells in a positive feedback loop.11 IL-4 induces TH2 cell differentiation in an autocrine manner at inflammatory sites.12 TH2 cells gain full effector capacity in tissues by interacting with various local cells, including innate lymphoid cells and neurons, which produce TH2-promoting factors in response to allergens, helminths and other stimuli.2,10

In addition to TH2 cells, mast cells, eosinophils and basophils produce IL-4.13-15 Eosinophils produce IL-4 in the very early stage of the immune response in lymph nodes and tissues and can induce TH2 differentiation by antigen presentation to CD4+ T cells.10 Fibroblasts play an important role in normal tissue repair and the induction of fibrosis by directly depositing extra cellular matrix in response to various growth factors and cytokines, including TH2 cytokines.10 Macrophages that are activated by IL-4 and IL-13 have been reported to induce fibrosis by various mechanisms.

IL-4 is the most common cytokine produced by TH2 lymphocytes and the key cytokine that regulates TH2 cell polarization.12,16 In addition, IL-4/IL-4R signaling promotes B cell proliferation and stimulates immunoglobulin class-switching to IgE antibody, the major antibody in allergic reactions.12,16 Production of these cytokines by TH2 lymphocytes and other cells accounts for the activation of the mast cells, basophiles, eosinophiles and smooth muscle cell contraction as well as stimulation of B cell differentiation into IgE-producing plasma cells, thus promoting several allergic reactions including allergic rhinitis, anaphylaxis, atopic dermatitis and asthma.12,16,17 TH2 cells are often observed in tissues in allergic patients and are known to play critical roles in the pathogenesis of allergic diseases.9,12,18-22 Allergic diseases are characterized by aberrant activation of TH2 cells in response to innocuous environmental proteins (allergens)23 and subsequent production of Type 2 cytokines at sites of allergic inflammation.24,25 These reactions involve inflammatory mediators released in the early-phase reaction by mast cells and basophils, and allergen-specific TH2 lymphocytes.26 TH2 cells act synergistically with type 2 innate-like lymphoid cells activated during the acute phase. They recruit effector cells such as eosinophils, basophils, as well as other lymphocytes, to the site of allergen exposure.27-29 IL-4, IL-5, and IL-13 drive TH2 cells towards a specialized TH2A phenotype associated with persistent allergy and high cytokine expression.30,31

Asthma is a heterogeneous disease that can be classified into phenotypes and endotypes based upon clinical or biological characteristics.13,32-34 IL-4, along with IL-13, plays a key role in TH2 asthma.32 Over expression of IL-4 in asthmatics is associated with exacerbations, compromised lung function, airway remodeling and airway epithelium injury.35 Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is associated with TH2-dependent inflammation.33 IL-4 mediates pro-inflammatory functions in asthma, including induction of the expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium and mucus secretion.36,37 TH2 inflammation is characterized by elevations in absolute peripheral or sputum eosinophil counts and levels of IgE (total and allergen-specific) and fractional exhaled nitric oxide, which serve as biomarkers for the presence of this type of inflammation.13 Compared with healthy controls, children and adults with asthma have higher serum levels of IL-4,38,39 and higher IL-4 levels may differentiate individuals with atopic asthma from those with nonatopic asthma.38,39 Persistence of asthma in children and adults may be predicted by elevated levels of IL-4.19,20

IL-4 regulates the protective immune response against helminths and other extracellular parasites.3,7 Plasma levels of IL-4 have been reported to be elevated in patients with eosinophilic esophagitis, indicating the role of adaptive TH2 immunity in this disease.40 A meta-analysis found that elevated IL-4 was strongly associated with acute respiratory distress syndrome mortality.41

There have been extensive clinical trials targeting IL-4 for the treatment of asthma.24 Modulation of IL-4 signaling42 represents an important therapeutic approach to target the drivers of allergy and asthma.18,42-45 Dupilumab targets the shared receptor for IL-4 and IL-13 and is approved for treatment of atopic dermatitis and asthma.2 Dupilumab has been shown to provide efficacy in the treatment of moderate-to-severe atopic dermatitis, allergic asthma, chronic rhinosinusitis and eosinophilic esophagitis, all known to be driven largely by type 2 inflammation.18,43-45

IL-4 and IL-13 produced by TH2 cells activate macrophages and epithelial cells and enhance the production of extracellular matrix, an element crucial for tissue repair.10 However, when the tissue repair process becomes chronic, excessive or uncontrolled, it may induce the development of pathological fibrosis in various organ systems.10 It was recently shown that TH2 cells include pathogenic TH2 (Tpath2) cells that highly express the receptor for IL-33 (a cytokine that is released during tissue injury) and produce large amounts of IL-5.9,10


Footnotes

1. Liu C, Chu D, Kalantar-Zadeh K, George J, Young HA, Liu G. Cytokines: from clinical significance to quantification. Adv Sci (Weinh). 2021 Aug;8(15):e2004433.34114369
2. Chopp L, Redmond C, O'Shea JJ, Schwartz DM. From thymus to tissues and tumors: A review of T-cell biology. J Allergy Clin Immunol. 2023 Jan;151(1):81-97. Epub 2022 Oct 19.36272581
3. Akdis M, Aab A, Altunbulakli C, et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2016 Oct;138(4):984-1010.27577879
4. Finkelman FD, Katona IM, Urban JF Jr, et al. IL-4 is required to generate and sustain in vivo IgE responses. J Immunol. 1988 Oct 1;141:2335-2341.2459206
5. Chen L, Grabowski KA, Xin JP, et al. IL-4 induces differentiation and expansion of Th2 cytokine-producing eosinophils. J Immunol. 2004 Feb 15;172(4):2059-2066.14764670
6. Ho IC, Miaw SC. Regulation of IL-4 expression in immunity and diseases. Adv Exp Med Biol. 2016;941:31-77.27734408
7. Haase P, Voehringer D. Regulation of the humoral type 2 immune response against allergens and helminths. Eur J Immunol. 2021 Feb;51(2):273-279.33305358
8. Justiz Vaillant AA, Qurie A. Interleukin. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan, 2022 Aug 22.29763015
9. Nakayama T, Hirahara K, Onodera A, et al. Th2 cells in health and disease. Annu Rev Immunol. 2017 Apr 26;35:53-84.27912316
10. Kokubo K, Onodera A, Kiuchi M, Tsuji K, Hirahara K, Nakayama T. Conventional and pathogenic Th2 cells in inflammation, tissue repair, and fibrosis. Front Immunol. 2022 Aug 9;13:945063.36016937
11. Yamane H, Paul WE. Cytokines of the γ(c) family control CD4+ T cell differentiation and function. Nat Immunol. 2012 Nov;13(11):1037-1044.23080204
12. Walker JA, McKenzie ANJ. T(H)2 cell development and function. Nat Rev Immunol. 2018 Feb;18:121-133.29082915
13. Busse WW, Viswanathan R. What has been learned by cytokine targeting of asthma? J Allergy Clin Immunol. 2022 Aug;150(2):235-249.35934678
14. Gadani SP, Cronk JC, Norris GT, Kipnis J. IL-4 in the brain: a cytokine to remember. J Immunol. 2012 Nov 1;189(9):4213-4219.23087426
15. Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol. 2015 Mar;135(3):626-635.25528359
16. Kubo M. T follicular helper and T(H)2 cells in allergic responses. Allergol Int. 2017 Jul;66(3):377-381.28499720
17. Saggini A, Maccauro G, Tripodi D, et al. Allergic inflammation: role of cytokines with special emphasis on IL-4. Int J Immunopathol Pharmacol. 2011 Apr-Jun;24(2):305-311.21658305
18. Geba GP, Li D, Xu M, et al. Attenuating the atopic march: meta-analysis of the dupilumab atopic dermatitis database for incident allergic events. J Allergy ClinImmunol. 2023 Mar;151(3):756-7669. Epub 2022 Sep 7.36084766
19. Wallrapp A, Riesenfeld SJ, Burkett PR, Kuchroo VK. Type 2 innate lymphoid cells in the induction and resolution of tissue inflammation. Immunol Rev. 2018 Nov;286(1):53-73.30294962
20. Hammad H, Debeuf N, Aegerter H, Brown AS, Lambrecht BN. Emerging paradigms in type 2 immunity. Annu Rev Immunol. 2022 Apr 26;40:443-467.35471837
21. Shankar A, McAlees JW, Lewkowich IP. Modulation of IL-4/IL-13 cytokine signaling in the context of allergic disease. J Allergy Clin Immunol. 2022 Aug;150(2):266-276.35934680
22. Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med. 1997 Dec;337(24):1720-1725.9392697
23. Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010 Jul;11(7):577-584.2056284
24. Chung KF, Barnes PJ. Cytokines in asthma. Thorax. 1999 Sep;54(9):825-857.10456976
25. Liu W, Liu S, Verma M, et al. Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma. J Allergy Clin Immunol. 2017 May;139(5):1548-1558.e4.27702673
26. Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008 Jul 24;454(7203):445-454.18650915
27. Bartemes KR, Kita H. Roles of innate lymphoid cells (ILCs) in allergic diseases: the 10-year anniversary for ILC2s. J Allergy Clin Immunol. 2021 May;147(5):1531-1547.33965091
28. Al-Shaikhly T, Murphy RC, Parker A, et al. Location of eosinophils in the airway wall is critical for specific features of airway hyper responsiveness and T2 inflammation in asthma. Eur Respir J. 2022 Aug 4;60(2):2101865.35027395
29. Dubin C, Del Duca E, Guttman-Yassky E. The IL-4, IL-13 and IL-31 pathways in atopic dermatitis. Expert Rev Clin Immunol. 2021 Aug;17(8):835-852.34106037
30. Bangert C, Rindler K, Krausgruber T, et al. Persistence of mature dendritic cells, TH2A,and Tc2 cells characterize clinically resolved atopic dermatitis under IL-4 Ralpha blockade. Sci Immunol. 2021 Jan 22;6(55):eabe2749.33483337
31. Koenig JFE, Bruton K, Phelps A, Grydziuszko E, Jiménez-Saiz R, Jordana M. Memory generation and re-activation in food allergy. Immunotargets Ther. 2021 Jun 9;10:171-184.34136419
32. Parulekar AD, Kao CC, Diamant Z, Hanania NA. Targeting the interleukin-4 and interleukin-13 pathways in severe asthma: current knowledge and future needs. Curr Opin Pulm Med. 2018 Jan;24(1):50-55.29036019
33. Habib N, Pasha MA, Tang DD. Current understanding of asthma pathogenesis and biomarkers. Cells. 2022 Sep 5;11(17):2764.36078171
34. Hammad H, Lambrecht BN. The basic immunology of asthma. Cell. 2021 Mar 18;184(6):1469-1485.33711259
35. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016 Jan;15(1):35-50.26471366
36. Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):66-70.11686867
37. Rosenberg HF, Phipps S, Foster PS. Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol. 2007 Jun;119:1303-1310; quiz 1311-1312.17481712
38. Hasegawa T, Uga H, Mori A, Kurata H. Increased serum IL-17A and Th2 cytokine levels in patients with severe uncontrolled asthma. Eur Cytokine Netw. 2017 Mar 1;28(1):8-18.28840844
39. Lama M, Chatterjee M, Nayak CR, Chaudhuri TK. Increased interleukin-4 and decreased interferon-γ levels in serum of children with asthma. Cytokine. 2011 Sep;55(3):335-338.21658970
40. Blanchard C, Stucke EM, Rodriguez-Jimenez B, et al. A striking local esophageal cytokine expression profile in eosinophilic esophagitis. J Allergy Clin Immunol. 2011 Jan;127(1):208-217, 217.e1-7.21211656
41. Terpstra ML, Aman J, van Nieuw Amerongen GP, Groeneveld AB. Plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis*. Crit Care Med. 2014 Mar;42(3):691-700.24158164
42. Luzina IG, Keegan AD, Heller NM, Rook GAW, Shea-Donohue T, Atamas SP. Regulation of inflammation by interleukin-4: a review of ‘‘alternatives.’’ J Leukoc Biol. 2012 Oct;92(4):753-764.22782966
43. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to severeun controlled asthma. N Engl J Med. 2018 Jun 28;378(26):2486-2496.29782217
44. Hirano I, Dellon ES, Hamilton JD, et al. Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology. 2020 Jan;158(1):111-122.e10.31593702
45. Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTYNP SINUS-52): results from two multicentre, randomised, double-blind, placebo controlled,parallel-group phase 3 trials. Lancet. 2019 Nov 2;394(10209):1638-1650.31543428

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
140814 Interleukin-4, Plasma 27161-9 140815 Interleukin-4, Plasma pg/mL 27161-9

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