Transcription Factor and Cytokine Profiles in Peripheral Blood T Helper Cells in Patients with Idiopathic Pulmonary Fibrosis
-
Neda Dalil Roofchayee
,
Jalal Heshmatnia
,
Hamidreaza Jamatti
,
Mohammad Varahram
,
Ian M Adcock
,
Esmaeil Mortaz
Abstract
Idiopathic pulmonary fibrosis (IPF) is a severe lung disease with a poor prognosis, characterized by immune cell activation. The role of T helper (Th) cell transcription factors in IPF pathogenesis remains unclear. In this study, we investigated Th cell transcription factors and related cytokines in IPF patients.
Twelve IPF patients and eight healthy controls (HC) were enrolled in this pilot study. Serum levels of fibrosis-associated mediators (Interferon-inducible protein 10 (IP-10), tumor necrosis factor-α (TNF-α), tumor growth factor-β (TGF-β), CXCL-8, interferon-γ (IFN-γ)) were measured by enzyme-linked immunosorbent assay (ELISA). Flow cytometry assessed Th transcription factors T box transcription factor (T-bet,), GATA-binding protein 3 (GATA-3), Retinoic acid-related orphan recepto (ROR-γt), forkhead box P3 (FOXP3)) and intracellular cytokines (IL-4, IL-17).
SerumTGF-β, CXCL-8, TNF-α, and IFN-γ were significantly elevated, while IP-10 (pT-bet, GATA3, ROR-γt, or FOXP3 were observed. Positive correlations were found between T-bet and GATA3, IL-4, ROR-γt, and TNF-α expression with age, while FOXP3 expression negatively correlated with age.
T-cell transcription factors were unchanged in IPF despite changes in inflammatory protein expression. Reduced IP-10 may serve as a potential marker.
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8. Wynn TA. Fibrotic disease and the Th1/Th2 paradigm. Nat Rev Immunol. 2004;4(8):583–94.
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15. Nakamura Y, Ghaffar O, Olivenstein R, Taha RA, Soussi‑Gounni A, Zhang D‑H, et al. Gene expression of the GATA‑3 transcription factor is increased in atopic asthma. J Allergy Clin Immunol. 1999;103(2):215–22.
16. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T‑bet, directs Th1 lineage commitment. Cell. 2000;100(6):655–69.
17. Zhou M, Ouyang W. The functional role of GATA‑3 in Th1 and Th2 differentiation. Immunol Res. 2003;28(1):25–37.
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22. Ramani K, Biswas PS. Interleukin‑17: friend or foe in organ fibrosis. Cytokine. 2019;120:282–8.
23. Shi T, Xie Y, Fu Y, Zhou Q, Ma Z, Ma J, et al. The signaling axis of microRNA‑31/interleukin‑25 regulates Th1/Th17‑mediated inflammation response in colitis. Mucosal Immunol. 2017;10(4):983–95.
24. Latella G, Viscido A. Controversial contribution of Th17/IL‑17 toward the immune response in intestinal fibrosis. Dig Dis Sci. 2020;65(5):1299–306.
25. Ma H, Liu S, Li S, Xia Y. Targeting growth factor and cytokine pathways to treat idiopathic pulmonary fibrosis. Front Pharmacol. 2022;13:918771.
26. Car BD, Meloni F, Luisetti M, Semenzato G, Gialdroni‑Grassi G, Walz A. Elevated IL‑8 and MCP‑1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J Respir Crit Care Med. 1994;149(3):655–9.
27. Guiot J, Henket M, Corhay J‑L, Moermans C, Louis R. Sputum biomarkers in IPF: evidence for raised gene expression and protein level of IGFBP‑2, IL‑8 and MMP‑7. PLoS One. 2017;12(2)\:e0171344.
28. Carre PC, Mortenson R, King T, Noble P, Sable C, Riches D. Increased expression of the interleukin‑8 gene by alveolar macrophages in idiopathic pulmonary fibrosis: a potential mechanism for the recruitment and activation of neutrophils in lung fibrosis. J Clin Invest. 1991;88(6):1802–10.
29. Lynch J, Standiford TJ, Rolfe MW, Kunkel SL, Strieter RM. Neutrophilic alveolitis in idiopathic pulmonary fibrosis. Am Rev Respir Dis. 1992;145(6):1433–9.
30. Ziora D, Jastrzębski D, Adamek M, Czuba Z, Grzanka A, Kasperska‑Zajac A. Circulating concentration of markers of angiogenic activity in patients with sarcoidosis and idiopathic pulmonary fibrosis. BMC Pulm Med. 2015;15:1.
31. Bringardner BD, Baran CP, Eubank TD, Marsh CB. The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis. Antioxid Redox Signal. 2008;10(2):287–302.
32. Hongbo Ma, Shengming Liu, Shanrui Li, Yong Xia. Targeting Growth Factor and Cytokine Pathways to Treat Idiopathic Pulmonary Fibrosis. Front Pharmacol. 2022:13:918771.
33. Hernandez DM, Kang J‑H, Choudhury M, Andrianifahanana M, Yin X, Limper AH, et al. IPF pathogenesis is dependent upon TGF‑β induction of IGF‑1. FASEB J. 2020;34(4):5363–88.
34. Oikonomou N, Harokopos V, Zalevsky J, Valavanis C, Kotanidou A, Szymkowski DE, et al. Soluble TNF mediates the transition from pulmonary inflammation to fibrosis. PLoS One. 2006;1(1)\:e108.
35. Gao B, Lin J, Jiang Z, Yang Z, Yu H, Ding L, et al. Upregulation of chemokine CXCL10 enhances chronic pulmonary inflammation in tree shrew collagen‑induced arthritis. Sci Rep. 2018;8(1):9993.
36. Keane MP, Belperio JA, Arenberg DA, Burdick MD, Xu ZJ, Xue YY, et al. IFN‑γ‑inducible protein‑10 attenuates bleomycin‑induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol. 1999;163(10):5686–92.
37. Keane MP, Arenberg JA, Lynch JP 3rd, Whyte RI, Iannettoni MD, Burdick MD, et al. The CXC chemokines, IL‑8 and IP‑10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol. 1997;159(3):1437–43.
38. Nie YJ, Wu SH, Xuan YH, Yan G. Role of IL‑17 family cytokines in the progression of IPF from inflammation to fibrosis. Mil Med Res. 2022;9(1):21.
39. Beringer A, Noack M, Miossec P. IL‑17 in chronic inflammation: from discovery to targeting. Trends Mol Med. 2016;22(3):230.
2. Ryu JH, Colby TV, Hartman TE, editors. Idiopathic pulmonary fibrosis: current concepts. Rochester (MN): Mayo Clin Proc; 1998.
3. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med. 2000;161:646–64.
4. Shenderov K, Collins SL, Powell JD, Horton MR. Immune dysregulation as a driver of idiopathic pulmonary fibrosis. J Clin Invest. 2021;131(2).
5. Desai O, Winkler J, Minasyan M, Herzog EL. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis. Front Med (Lausanne). 2018;5:43.
6. Nuovo GJ, Hagood JS, Magro CM, Chin N, Kapil R, Davis L, et al. The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis. Mod Pathol. 2012;25(3):416–33.
7. Deng L, Huang T, Zhang L. T cells in idiopathic pulmonary fibrosis: crucial but controversial. Cell Death Discov. 2023;9(1):62.
8. Wynn TA. Fibrotic disease and the Th1/Th2 paradigm. Nat Rev Immunol. 2004;4(8):583–94.
9. Schrier DJ, Phan SH, McGarry BM. The effects of the nude (nu/nu) mutation on bleomycin-induced pulmonary fibrosis: a biochemical evaluation. Am Rev Respir Dis. 1983;127(5):614–7.
10. Saito A, Okazaki H, Sugawara I, Yamamoto K, Takizawa H. Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro. Int Arch Allergy Immunol. 2003;132(2):168–76.
11. Rottoli P, Magi B, Perari MG, Liberatori S, Nikiforakis N, Bargagli E, et al. Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics. 2005;5(5):1423–30.
12. Spagnolo P, Tonelli R, Samarelli AV, Castelli G, Cocconcelli E, Petrarulo S, et al. The role of immune response in the pathogenesis of idiopathic pulmonary fibrosis: far beyond the Th1/Th2 imbalance. Expert Opin Ther Targets. 2022;26(7):617–31.
13. Sumida A, Hasegawa Y, Okamoto M, Hashimoto N, Imaizumi K, Yatsuya H, et al. Th1/Th2 immune response in lung fibroblasts in interstitial lung disease. Arch Med Res. 2008;39(5):503–10.
14. Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH, et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science. 2002;295(5553):336–8.
15. Nakamura Y, Ghaffar O, Olivenstein R, Taha RA, Soussi‑Gounni A, Zhang D‑H, et al. Gene expression of the GATA‑3 transcription factor is increased in atopic asthma. J Allergy Clin Immunol. 1999;103(2):215–22.
16. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T‑bet, directs Th1 lineage commitment. Cell. 2000;100(6):655–69.
17. Zhou M, Ouyang W. The functional role of GATA‑3 in Th1 and Th2 differentiation. Immunol Res. 2003;28(1):25–37.
18. King TE, Albera C, Bradford WZ, Costabel U, Hormel P, Lancaster L, et al. Effect of interferon gamma‑1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo‑controlled trial. Lancet. 2009;374(9685):222–8.
19. Bergeron A, Soler P, Kambouchner M, Loiseau P, Milleron B, Valeyre D, et al. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF‑β and IL‑10. Eur Respir J. 2003;22(1):69–76.
20. Tsoutsou PG, Gourgoulianis KI, Petinaki E, Germenis A, Tsoutsou AG, Mpaka M, et al. Cytokine levels in the sera of patients with idiopathic pulmonary fibrosis. Respir Med. 2006;100(5):938–45.
21. Papiris SA, Tomos IP, Karakatsani A, Spathis A, Korbila I, Analitis A, et al. High levels of IL‑6 and IL‑8 characterize early‑on idiopathic pulmonary fibrosis acute exacerbations. Cytokine. 2018;102:168–72.
22. Ramani K, Biswas PS. Interleukin‑17: friend or foe in organ fibrosis. Cytokine. 2019;120:282–8.
23. Shi T, Xie Y, Fu Y, Zhou Q, Ma Z, Ma J, et al. The signaling axis of microRNA‑31/interleukin‑25 regulates Th1/Th17‑mediated inflammation response in colitis. Mucosal Immunol. 2017;10(4):983–95.
24. Latella G, Viscido A. Controversial contribution of Th17/IL‑17 toward the immune response in intestinal fibrosis. Dig Dis Sci. 2020;65(5):1299–306.
25. Ma H, Liu S, Li S, Xia Y. Targeting growth factor and cytokine pathways to treat idiopathic pulmonary fibrosis. Front Pharmacol. 2022;13:918771.
26. Car BD, Meloni F, Luisetti M, Semenzato G, Gialdroni‑Grassi G, Walz A. Elevated IL‑8 and MCP‑1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J Respir Crit Care Med. 1994;149(3):655–9.
27. Guiot J, Henket M, Corhay J‑L, Moermans C, Louis R. Sputum biomarkers in IPF: evidence for raised gene expression and protein level of IGFBP‑2, IL‑8 and MMP‑7. PLoS One. 2017;12(2)\:e0171344.
28. Carre PC, Mortenson R, King T, Noble P, Sable C, Riches D. Increased expression of the interleukin‑8 gene by alveolar macrophages in idiopathic pulmonary fibrosis: a potential mechanism for the recruitment and activation of neutrophils in lung fibrosis. J Clin Invest. 1991;88(6):1802–10.
29. Lynch J, Standiford TJ, Rolfe MW, Kunkel SL, Strieter RM. Neutrophilic alveolitis in idiopathic pulmonary fibrosis. Am Rev Respir Dis. 1992;145(6):1433–9.
30. Ziora D, Jastrzębski D, Adamek M, Czuba Z, Grzanka A, Kasperska‑Zajac A. Circulating concentration of markers of angiogenic activity in patients with sarcoidosis and idiopathic pulmonary fibrosis. BMC Pulm Med. 2015;15:1.
31. Bringardner BD, Baran CP, Eubank TD, Marsh CB. The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis. Antioxid Redox Signal. 2008;10(2):287–302.
32. Hongbo Ma, Shengming Liu, Shanrui Li, Yong Xia. Targeting Growth Factor and Cytokine Pathways to Treat Idiopathic Pulmonary Fibrosis. Front Pharmacol. 2022:13:918771.
33. Hernandez DM, Kang J‑H, Choudhury M, Andrianifahanana M, Yin X, Limper AH, et al. IPF pathogenesis is dependent upon TGF‑β induction of IGF‑1. FASEB J. 2020;34(4):5363–88.
34. Oikonomou N, Harokopos V, Zalevsky J, Valavanis C, Kotanidou A, Szymkowski DE, et al. Soluble TNF mediates the transition from pulmonary inflammation to fibrosis. PLoS One. 2006;1(1)\:e108.
35. Gao B, Lin J, Jiang Z, Yang Z, Yu H, Ding L, et al. Upregulation of chemokine CXCL10 enhances chronic pulmonary inflammation in tree shrew collagen‑induced arthritis. Sci Rep. 2018;8(1):9993.
36. Keane MP, Belperio JA, Arenberg DA, Burdick MD, Xu ZJ, Xue YY, et al. IFN‑γ‑inducible protein‑10 attenuates bleomycin‑induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol. 1999;163(10):5686–92.
37. Keane MP, Arenberg JA, Lynch JP 3rd, Whyte RI, Iannettoni MD, Burdick MD, et al. The CXC chemokines, IL‑8 and IP‑10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol. 1997;159(3):1437–43.
38. Nie YJ, Wu SH, Xuan YH, Yan G. Role of IL‑17 family cytokines in the progression of IPF from inflammation to fibrosis. Mil Med Res. 2022;9(1):21.
39. Beringer A, Noack M, Miossec P. IL‑17 in chronic inflammation: from discovery to targeting. Trends Mol Med. 2016;22(3):230.
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| Cytokines FOXP3 GATA-3 IPF ROR-γt T-bet | ||
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How to Cite
1.
Dalil Roofchayee N, Heshmatnia J, Jamatti H, Varahram M, Adcock I, Mortaz E. Transcription Factor and Cytokine Profiles in Peripheral Blood T Helper Cells in Patients with Idiopathic Pulmonary Fibrosis. Iran J Allergy Asthma Immunol. 2025;:1-13.
