Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1 (5-Year IF – 2.0)
Journal Citation Indicator (JCI) (2023) – 0.4
Scopus CiteScore – 3.7 (CiteScore Tracker – 4.3)
Index Copernicus  – 171.00; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2009, vol. 18, nr 6, November-December, p. 559–565

Publication type: original article

Language: English

Association of Soluble IL−4R Serum Levels and IL−4Rα Chain Gene Polymorphisms

Stężenie rozpuszczalnej formy receptora IL−4 w odniesieniu do polimorfizmu genu IL−4Rα

Hanna Danielewicz1,, Magdalena Hurkacz2,, Andrzej Boznański1,, Annawiela−hojeńsk Annawiela−Hojeńska2,, Anna Chamerska−Drabik1,

1 First Department and Clinic of Pediatrics, Allergology, and Cardiology, Wroclaw Medical University, Poland

2 Chair and Department of Clinical Pharmacology, Wroclaw Medical University, Poland

Abstract

Background. The IL−4 receptor plays a key role in IL−4 signal transmission, immunoglobulin isotype switching, and Th2 differentiation. These processes are directly associated in the response to allergens and chronic allergic inflammation. Soluble sIL−4R is part of the homeostatic mechanism for IL−4. With an appropriate sIL−4R/IL−4 ratio, it can act as an IL−4 inhibitor; this mechanism was implemented in innovative asthma therapy. Polymorphisms in the IL−4Rα gene, among others C−3223T and I50V, have been reported to be associated with atopy. They may potentially affect the function of the gene and the decoded protein.
Objectives. The aim of the study was to analyze the serum levels of sIL−4R in children and adults in relation to atopy and C−3223T and I50V genotype.
Material and Methods. Serum levels of sIL−4R were determined by ELISA in children and adults (n = 106) previously genotyped for both polymorphisms.
Results. The study found statistically significant differences in the level of sIL−4R in relation to genotype in the group of children (p < 0.05, Whitney−Mann U test). The atopic children had lower levels of sIL−4R than controls, although the results were not statistically significant. In the adults there were no statistical significant differences in serum sIL−4R levels.
Conclusion. The findings point to a potentially significant role of C−3223T and possibly of I50V in the negative regulation of the IL−4 pathway.

Streszczenie

Wprowadzenie. Receptor dla IL−4 pełni kluczową rolę w przekazywaniu sygnału związanego z IL−4, a tym samym w procesie przełączania klas immunoglobulin oraz przekierowaniu odpowiedzi układu immunologicznego w kierunku Th2. Procesy te są związane bezpośrednio zarówno z reakcją organizmu na alergeny, jak i utrzymywaniem się stanu przewlekłego zapalenia alergicznego. Rozpuszczalna forma receptora dla IL−4 (sIL−4R) jest elementem układu homeostatycznego dla IL−4. Przy odpowiednim stosunku stężeń obu czynników może pełnić funkcję hamującą działanie IL−4, który to mechanizm wykorzystano w innowacyjnych formach terapii astmy. Polimorfizmy w regionie genu dla łańcucha alfa receptora IL−4, między innymi C−3223T i I50V, zostały opisane jako czynniki związane z występowaniem atopii. Potencjalnie mogą wpływać na funkcje genu oraz kodowanego białka.
Cel pracy. Analiza surowiczych stężeń sIL−4R u dzieci oraz osób dorosłych w odniesieniu do cech atopii i wymienionych genotypów.
Materiał i metody. Surowicze stężenia sIL−4R oznaczono z wykorzystaniem techniki ELISA w grupie dzieci i osób dorosłych (n = 106), u których pierwotnie oznaczono genotyp dla obu polimorfizmów.
Wyniki. Wykazano różnice w stężeniach sIL−4R w grupie dzieci w odniesieniu do genotypów (p < 0,05, Whitney−Mann U rank test). U dzieci z atopią obserwowano mniejsze stężenia sIL−4R w porównaniu z grupą kontrolną, różnice jednak były nieistotne statystycznie. W grupie dorosłych nie wykazano również statystycznie istotnych różnic w stężeniach sIL−4R.
Wnioski. Uzyskane wyniki potencjalnie wskazują na znaczącą rolę C−3223T oraz I50 V w regulacji immunologicznej związanej z IL−4.

Key words

sIL−4R, IL−4Rα gene promoter, genetic polymorphism

Słowa kluczowe

sIL−4R, promotor genu IL−4Rα, polimorfizm genetyczny

References (26)

  1. Boznański A, Machnicki M: Zachowanie się intreferonu−γ i interleukiny−4 w stymulowanych hodowlach komórkowych u dzieci z astmą oskrzelową i atopowym zapaleniem skóry. Post Med Klin Doś 1993, 2, 33–38.
  2. Borres MP, Einarsson R, Bjorksten B: Serum levels of interleukin−4, soluble CD23 and IFN gamma in relation to the development of allergic disease during the first 18 months of life. Clin Exp Allergy 1995, 25, 543–548.
  3. Daher S, Santos LM, Sole D, De Lima MG, Naspitz CK, Musatti CC: Interlukin 4 and soluble CD23 serum levels in atopic asthmatic children. J Invest Allergol Clin Immunol 1995, 5. 251–254.
  4. Brightling CE, Symon FA, Birring SS, Bradding P, Pavord ID, Wardlaw AJ: TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophylic bronchitis. J Allergy Clin Immunol 2002, 110, 899–905.
  5. Humbert M, Durham SR, Ying S, Kimmitt P, Barkans J, Assoufi B, Pfister R, Menz G, Robinson DS, Kay AB, Corrigan CJ: IL−4 and IL−5 mRNA and protein in bronchial biopsies from patients witha atopic and non atopic asthma: evidence against intrinsic asthma being a distinct immunopathologic entity. Am J Respir Crit Care Med 1996, 154, 1497–1504.
  6. Kimura M, Tsuruta S, Yoshida T: IL−4 production by PBMCs on stimulation with mite allergen is correlated with the level of serum IgE antibody against mite in children with bronchial asthma. J Allergy Clin Immunol 2000, 105, 327–332.
  7. Chan CS, Brown MA, Willcox TM, Li SH, Stevens SR, Tara D, Hanifin JM: Abnormal IL−4 gene expression by atopic dermatitis T lymphocytes is reflected in altered nuclear protein interactions with IL−4 regulatory element. J Invest Dermatol 1996, 106, 1131–1136.
  8. Kotsimbos TC, Ghaffar EM, Minshall M, Humbert M, Durham SR, Pfister R, Menz G, Kay AB, Hamid QA: Expression of IL−4receptor alpha−subunit is increased in bronchial biopsy specimens from atopic and nonatopic asthmatic subjects. J Allergy Clin Immunol 1998, 102, 859–866.
  9. Kowal K, Osada J, Zukowski S, Dabrowska M, Dubuske L, Bodzenta−Lukaszyk A: Expression of interleukin 4 receptors in bronchial asthma patients who underwent specific immunotherapy. Ann Allergy Asthma Immunol 2004, 93(1), 68–75.
  10. Fujita N, Okamoto Y, Gotoh Y, Yada Y, Suzuki Y, Ando T, Togari H, Nishida M: Serum evaluation of the balance between soluble interleukin−2 and interleukin−4 receptors. Cytokine 2005 Nov 3, 32(3–4), 143–148. Epub 2005 Oct 13.
  11. Schauer U, Schmitt M, Muller S, Enssle K, Kurrle R, Sundermann U, Bender A, Wahn U, Reiger CH: Soluble interleukin 4 receptor in atopic children. Int Arch Allergy Immunol 1995, 108, 175–182.
  12. Benson M, Wennergren G, Fransson M, Cardell LO: Altered levels of the soluble IL−1, IL−4 and TNF receptors, as well as the IL−1 receptor antagonist, in intermittent allergic rhinitis. Int Arch Allergy Immunol 2004, 134, 227–232.
  13. Boznański A, Willak−Janc E, Persona−Jakimiec B, Hebrowska A, Drabik A: The influence of immunotherapy on IL−4 receptor expression in children with pollinosis. Abstract No W 99. International Congress of Allergology and Clinical Immunology, Sydney 12–18 Oct. 2000.
  14. Hackstein H, Hecker M, Kruse S, Bohnert A, Ober C, Deichmann KA, Bein G: A novel polymorphism in the 5’ promoter region of the human interleukin−4 receptor alpha−chain gene is associated with decreased soluble interleukin−4 receptor protein levels. Immunogenetics 2001, 53, 264–269.
  15. Danielewicz H, Hurkacz M, Boznański A, Wiela−Hojeńska A: Polymorphism in the promoter and coding regions of the IL−4 receptor alpha−chain gene in atopic children, Adv Clin Exp Med 2007, 16, 6, 735–741.
  16. Borish L, Stienke J: Cytokines and chemokines. J Allergy Clin Immunol 2003, 11, 460–475.
  17. Howard TD, Koppelmann GH, Xu GH, Zheng SL, Postma DS, Meyers DA, Bleecker ER: Gene−gene interaction in asthma: IL4RA and IL13 in Dutch population with asthma. Am J Hum Genet 2002, 70, 230–236.
  18. Ober C, Leavitt SA, Tsalenko A, Howard TD, Hoki DM, Daniel R, Newman DL, Wu X, Parry R, Lester LA, Solway J, Blumenthal M, King RA, Xu J, Meyers DA, Blecker ER, Cox NJ: Variation in the interleukin 4− receptor gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet 2000, 66, 517–526.
  19. Hytonen AM, Lowhagen O, Arvidsson M, Balder B, Bjork AL, Lindgren S, Hahn−Zoric M, Hanson LA, Padyukov L: Haplotypes of the interleukin−4 receptor alpha chain gene associate with susceptibility to and severity of atopic asthma. Clin Exp Allergy 2004, 34, 1570–1575.
  20. Fukai K, Hosomi N, Oiso N, Kato A, Ishii M, Kunimoto H, Nakajima K: Polymorphisms in the promoter of the interleukin−4 receptor alpha chain gene are associated with atopic dermatitis in Japan. J Dermatol Sci 2004 Jun, 35(1), 78–80.
  21. O’Byrne PM: Cytokines or their antagonists for the treatment of asthma. Chest 2006 Jul, 130(1), 244–250.
  22. Zavorotinskaya T, Tomkinson A, Murphy J: Treatment of experimental asthma by long−term gene therapy directed against IL−4 and IL−13. Mol Ther 2003, 7, 155–162.
  23. Grunewald SM, Kunzmann S, Schnarr B, Ezernieks J, Sebald W, Duschl A: A murine interleukin 4 antagonistic mutant protein completely inhibits interleukin−4 induced cell proliferatuion, differentiation and signal transduction. J Biol Chem 1997, 272, 1480–1483.
  24. Borish LC, Nelson HS, Lanz MJ, et al.: Interleukin−4 receptor in moderate atopic asthma: a phase I/II randomized, placebo−controlled trial. Am J Respir Crit Care Med 1999, 160, 1816–1823.
  25. Borish LC, Nelson HS, Corren J: Efficacy of soluble IL−4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001, 107, 963–970.
  26. Andrews AL, Holloway JW, Holgate ST, Davies DE: IL−4 Receptor alpha is an important modulator of IL−4 and IL−13 receptor binding: implications for the development of therapeutic targets. J Immunol 2006, Jun 15, 176(12), 7456–7461.
© Wroclaw Medical University