Log in

Cytokine signaling pathway in cystic fibrosis: expression of SOCS and STATs genes in different clinical phenotypes of the disease

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

This was an observational cross-sectional study which was done to assess the expression profile of STATs and SOCS genes in cystic fibrosis. The mRNA was isolated from peripheral blood mononuclear cells of CF patients in exacerbation, colonization and post exacerbation phases of the disease. The relative gene expression level for SOCS 1, -3, -5 and STAT 1, -3,-4,-6 genes was quantified by Real-time PCR. The levels of IL-6 were also measured in the serum by ELISA. The expression of the Th1 pathway associated genes (SOCS1, SOCS5, STAT4 and STAT1) was downregulated while the expression of Th2/Th17 pathway genes (SOCS3, STAT3, STAT6) was upregulated in both exacerbation and colonization phases as compared to healthy controls. The serum levels of IL-6 were also elevated in both the disease groups. After antibiotic treatment, the expression of SOCS5 and STAT4 was increased while the expression of rest of the genes showed downregulation which shows a shift in immune response from Th2/Th17 to Th1. Our results suggest that infection alters the cytokine signaling pathway through modulation of STATs and SOCS genes which is not able to regulate the overstimulation of cytokine signaling further leading to chronic inflammation in CF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

References

  1. Stoltz DA, Meyerholz DK, Welsh MJ (2015) Origins of cystic fibrosis lung disease. N Engl J Med 372(4):351–362. https://doi.org/10.1056/NEJMra1300109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Khoury O, Barrios C, Ortega V, Atala A, Murphy SV (2018) Immunomodulatory cell therapy to target cystic fibrosis inflammation. Am J Respir Cell Mol Biol 58(1):12–20. https://doi.org/10.1165/rcmb.2017-0160TR

    Article  CAS  PubMed  Google Scholar 

  3. Muhlebach MS, Stewart PW, Leigh MW, Noah TL (1999) Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients. Am J Respir Crit Care Med 160(1):186–191. https://doi.org/10.1164/ajrccm.160.1.9808096

    Article  CAS  PubMed  Google Scholar 

  4. Rapaka RR, Kolls JK (2009) Pathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis: current understanding and future directions. Med Mycol 47(Suppl 1):S331–S337. https://doi.org/10.1080/13693780802266777

    Article  CAS  PubMed  Google Scholar 

  5. De Rose V (2002) Mechanisms and markers of airway inflammation in cystic fibrosis. Eur Respir J 19(2):333–340. https://doi.org/10.1183/09031936.02.00229202

    Article  PubMed  Google Scholar 

  6. Bonfield TL, Panuska JR, Konstan MW, Hilliard KA, Hilliard JB, Ghnaim H et al (1995) Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med 152(6 Pt 1):2111–2118. https://doi.org/10.1164/ajrccm.152.6.8520783

    Article  CAS  PubMed  Google Scholar 

  7. Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264(5164):1415–1421. https://doi.org/10.1126/science.8197455

    Article  CAS  PubMed  Google Scholar 

  8. Elliott J, Johnston JA (2004) SOCS: role in inflammation, allergy and homeostasis. Trends Immunol 25(8):434–440. https://doi.org/10.1016/j.it.2004.05.012

    Article  CAS  PubMed  Google Scholar 

  9. Palmer DC, Restifo NP (2009) Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function. Trends Immunol 30(12):592–602. https://doi.org/10.1016/j.it.2009.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bilton D, Canny G, Conway S et al (2011) Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials. J Cyst Fibros 10(Suppl. 2):S79–S81. https://doi.org/10.1016/S1569-1993(11)60012-X

    Article  PubMed  Google Scholar 

  11. Moser C, Jensen PO, Kobayashi O, Hougen HP, Song Z, Rygaard J et al (2002) Improved outcome of chronic Pseudomonas aeruginosa lung infection is associated with induction of a Th1-dominated cytokine response. Clin Exp Immunol 127(2):206–213. https://doi.org/10.1046/j.1365-2249.2002.01731.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zuercher AW, Imboden MA, Jampen S, Bosse D, Ulrich M, Chtioui H et al (2006) Cellular immunity in healthy volunteers treated with an octavalent conjugate Pseudomonas aeruginosa vaccine. Clin Exp Immunol 143(1):132–138. https://doi.org/10.1111/j.1365-2249.2005.02964.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Toghi M, Taheri M, Arsang-Jang S, Ohadi M, Mirfakhraie R, Mazdeh M et al (2017) SOCS gene family expression profile in the blood of multiple sclerosis patients. J Neurol Sci 375:481–485. https://doi.org/10.1016/j.jns.2017.02.015

    Article  CAS  PubMed  Google Scholar 

  14. Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K et al (2003) SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med 9(8):1047–1054. https://doi.org/10.1038/nm896

    Article  PubMed  Google Scholar 

  15. Seki Y, Hayashi K, Matsumoto A, Seki N, Tsukada J, Ransom J et al (2002) Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation. Proc Natl Acad Sci USA 99(20):13003–13008. https://doi.org/10.1073/pnas.202477099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Eyles JL, Metcalf D, Grusby MJ, Hilton DJ, Starr R (2002) Negative regulation of interleukin-12 signaling by suppressor of cytokine signaling-1. J Biol Chem 277(46):43735–43740. https://doi.org/10.1074/jbc.M208586200

    Article  CAS  PubMed  Google Scholar 

  17. Heller NM, Matsukura S, Georas SN, Boothby MR, Rothman PB, Stellato C et al (2004) Interferon-gamma inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. Am J Respir Cell Mol Biol 31(5):573–582. https://doi.org/10.1165/rcmb.2004-0195OC

    Article  CAS  PubMed  Google Scholar 

  18. Ivanov II, Zhou L, Littman DR (2007) Transcriptional regulation of Th17 cell differentiation. Semin Immunol 19(6):409–417. https://doi.org/10.1016/j.smim.2007.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Johnson DE, O’Keefe RA, Grandis JR (2018) Targeting the il-6/jak/stat3 signalling axis in cancer. Nat Rev Clin Oncol 15:234–248. https://doi.org/10.1038/nrclinonc.2018.8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hanada T, Yoshida T, Kinjyo I, Minoguchi S, Yasukawa H, Kato S et al (2001) A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAB/CIS family proteins through the SOCS-box. J Biol Chem 276(44):40746–40754. https://doi.org/10.1074/jbc.M106139200

    Article  CAS  PubMed  Google Scholar 

  21. Tang AC, Saferali A, He G, Sandford AJ, Strug LJ, Turvey SE (2017) Endoplasmic reticulum stress and chemokine production in cystic fibrosis airway cells: regulation by STAT3 modulation. J Infect Dis 215(2):293–302. https://doi.org/10.1093/infdis/jiw516

    Article  CAS  PubMed  Google Scholar 

  22. Vella A et al (2020) mTOR and STAT3 pathway hyper-activation is associated with elevated interleukin-6 levels in patients with Shwachman-diamond syndrome: further evidence of lymphoid lineage impairment. Cancers 12:597. https://doi.org/10.3390/cancers12030597

    Article  CAS  PubMed Central  Google Scholar 

  23. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334(Pt 2):297–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Watford WT, Hissong BD, Durant LR, Yamane H, Muul LM, Kanno Y et al (2008) Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii. J Exp Med 205(12):2803–2812. https://doi.org/10.1084/jem.20081461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lieberman LA, Banica M, Reiner SL, Hunter CA (2004) STAT1 plays a critical role in the regulation of antimicrobial effector mechanisms, but not in the development of Th1-type responses during toxoplasmosis. J Immunol 172(1):457–463. https://doi.org/10.4049/jimmunol.172.1.457

    Article  CAS  PubMed  Google Scholar 

  26. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O’Shea JJ (2006) Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci 103:8137–8142. https://doi.org/10.1073/pnas.0600666103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Egwuagu CE, Yu CR, Zhang M, Mahdi RM, Kim SJ, Gery I (2002) Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. J Immunol 168(7):3181–3187. https://doi.org/10.4049/jimmunol.168.7.3181

    Article  CAS  PubMed  Google Scholar 

  28. Moss RB, Hsu YP, Olds L (2000) Cytokine dysregulation in activated cystic fibrosis (CF) peripheral lymphocytes. Clin Exp Immunol 120(3):518–525. https://doi.org/10.1046/j.1365-2249.2000.01232.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yamamoto K, Yamaguchi M, Miyasaka N, Miura O (2003) SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor b2 subunit. Biochem Biophys Res Commun 310:1188–1193. https://doi.org/10.1016/j.bbrc.2003.09.140

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was funded by Indian Council of Medical Research, New Delhi through Grant Number: ICMR JRF No. 3/1/3/JRF-2012 HRD-08 (10835) and Postgraduate Institute of Medical Education and Research, Chandigarh.

Author information

Authors and Affiliations

Authors

Contributions

SS was involved in conceptualizing the research proposal, performed all experimental procedures and wrote the manuscript. JK and RP provided the laboratory resources and helped in analysing the data. MS was responsible for patient recruitment, obtaining informed consent, data analysis and editing of the manuscript.

Corresponding author

Correspondence to Meenu Singh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sagwal, S., Prasad, R., Kaur, J. et al. Cytokine signaling pathway in cystic fibrosis: expression of SOCS and STATs genes in different clinical phenotypes of the disease. Mol Cell Biochem 476, 2869–2876 (2021). https://doi.org/10.1007/s11010-021-04051-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-021-04051-2

Keywords

Navigation