Expression of IL-21 and IL-33 in Intestinal Mucosa of Inflammatory Bowel Disease: An Immunohistochemical Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Collection
2.2. Study Groups
2.3. Immunohistochemistry
2.4. Statistical Analysis
3. Results
3.1. Duration of the Disease (Table 1)
Disease | Duration | Frequency | Percent |
---|---|---|---|
UC | <3 years | 11 | 22.4 |
>3 years | 38 | 77.6 | |
Total | 49 | 100.0 | |
CD | <3 years | 8 | 11.1 |
>3 years | 64 | 88.9 | |
Total | 72 | 100.0 |
3.2. IBD Phenotype
3.3. Activity of the Disease
3.3.1. Mayo Score for Colitis
3.3.2. Harvey-Bradshaw Index (H.B.I.) for Crohn’s Disease
3.4. Treatment Choices of IBD Patients
3.5. IL-21 Expression
3.5.1. A1: IL-21 Expression in IBD Group
3.5.2. A2: IL-21 Expression in UC and CD Patients
3.6. IL-33 Expression
3.6.1. B1: IL-33 Expression in IBD Patients
3.6.2. B2: IL-33 Expression in UC Patients
3.6.3. B3: IL-33 Expression in CD Patients
3.7. Intergroup Correlation in Interleukin Expression
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Yadav, P.K.; Chen, C.; Liu, Z. Potential Role of NK Cells in the Pathogenesis of Inflammatory Bowel Disease. J. Biomed. Biotechnol. 2011, 2011, 348530. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hollis-Moffatt, J.E.; Gearry, R.B.; Barclay, M.L.; Merriman, T.R.; Roberts, R.L. Consolidation of evidence for association of the KIAA1109-TENR-IL2-IL21 rs6822844 variant with Crohn’s disease. Am. J. Gastroenterol. 2010, 105, 1204–1205. [Google Scholar] [CrossRef] [PubMed]
- Monteleone, G.; Pallone, F.; MacDonald, T.T. Emerging immunological targets in inflammatory bowel disease. Curr. Opin. Pharmacol. 2011, 11, 640–645. [Google Scholar] [CrossRef]
- Kaistha, A.; Levine, J. Inflammatory Bowel Disease: The Classic Gastrointestinal Autoimmune Disease. Curr. Probl. Pediatr. Adolesc. Health Care 2014, 44, 328–334. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Jiang, X.; Zhu, J.; Yue, D.; Zhang, X.; Wang, X.; You, Y.; Wang, B.; Xu, Y.; Lu, C.; et al. IL-21/IL-21R signaling suppresses intestinal inflammation induced by DSS through regulation of Th responses in lamina propria in mice. Sci. Rep. 2016, 6, 31881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lopetuso, L.R.; Chowdhry, S.; Pizarro, T.T. Opposing Functions of Classic and Novel IL-1 Family Members in Gut Health and Disease. Front. Immunol. 2013, 4, 181. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hodzic, Z.; Schill, E.M.; Bolock, A.M.; Good, M. IL-33 and the intestine: The good, the bad, and the inflammatory. Cytokine 2017, 100, 1–10. [Google Scholar] [CrossRef]
- Bevivino, G.; Monteleone, G. Advances in understanding the role of cytokines in inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol. 2018, 12, 907–915. [Google Scholar] [CrossRef]
- Williams, M.A.; O’Callaghan, A.; Corr, S.C. IL-33 and IL-18 in Inflammatory Bowel Disease Etiology and Microbial Interactions. Front. Immunol. 2019, 10, 1091. [Google Scholar] [CrossRef] [Green Version]
- Nunes, T.; Bernardazzi, C.; De Souza, H.S. Interleukin-33 and Inflammatory Bowel Diseases: Lessons from Human Studies. Mediat. Inflamm. 2014, 2014, 423957. [Google Scholar] [CrossRef]
- Griesenauer, B.; Paczesny, S. The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases. Front. Immunol. 2017, 8, 475. [Google Scholar] [CrossRef] [Green Version]
- Pastorelli, L.; Garg, R.R.; Hoang, S.B.; Spina, L.; Mattioli, B.; Scarpa, M.; Fiocchi, C.; Vecchi, M.; Pizarro, T.T. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc. Natl. Acad. Sci. USA 2010, 107, 8017–8022. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Műzes, G.; Molnár, B.; Tulassay, Z.; Sipos, F. Changes of the cytokine profile in inflammatory bowel diseases. World J. Gastroenterol. 2012, 18, 5848–5861. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, Q.; Chen, G. Role of IL-33 and Its Receptor in T Cell-Mediated Autoimmune Diseases. BioMed Res. Int. 2014, 2014, 587376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pastorelli, L.; De Salvo, C.; Vecchi, M.; Pizarro, T.T. The Role of IL-33 in Gut Mucosal Inflammation. Mediat. Inflamm. 2013, 2013, 608187. [Google Scholar] [CrossRef] [Green Version]
- Fina, D.; Sarra, M.; Fantini, M.C.; Rizzo, A.; Caruso, R.; Caprioli, F. Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology 2008, 134, 1038–1048. [Google Scholar] [CrossRef]
- Liu, Z.; Yang, L.; Cui, Y.; Wang, X.; Guo, C.; Huang, Z.; Kan, Q.; Liu, Z.; Liu, Y. Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease. Inflamm. Bowel Dis. 2009, 15, 1133–1144. [Google Scholar] [CrossRef]
- Liu, C.; Xia, X.; Wu, W.; Wu, R.; Tang, M.; Chen, T. Anti-tumour necrosis factor therapy enhances mucosal healing through down-regulation of interleukin-21 expression and T helper type 17 cell infiltration in Crohn’s disease. Clin. Exp. Immunol. 2013, 173, 102–111. [Google Scholar] [CrossRef]
- Jiang, W.; Su, J.; Zhang, X.; Cheng, X.; Zhou, J.; Shi, R.; Zhang, H. Elevated levels of Th17 cells and Th17-related cytokines are associated with disease activity in patients with inflammatory bowel disease. Inflamm. Res. 2014, 63, 943–950. [Google Scholar] [CrossRef]
- Holm, T.L.; Tornehave, D.; Søndergaard, H.; Kvist, P.H.; Sondergaard, B.-C.; Hansen, L.; Hermit, M.B.; Holgersen, K.; Vergo, S.; Frederiksen, K.S.; et al. Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease. Gastroenterol. Res. Pr. 2018, 2018, 5962624. [Google Scholar] [CrossRef] [Green Version]
- Sarra, M.; Monteleone, I.; Stolfi, C.; Fantini, M.C.; Sileri, P.; Sica, G.; Tersigni, R.; Macdonald, T.T.; Pallone, F.; Monteleone, G. Interferon-gamma-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases. Inflamm. Bowel Dis. 2010, 16, 1332–1339. [Google Scholar] [CrossRef]
- De Souza, H.; Fiocchi, C. Immunopathogenesis of IBD: Current state of the art. Nat. Rev. Gastroenterol. Hepatol. 2015, 13, 13–27. [Google Scholar] [CrossRef]
- Pallone, F.; Fina, D.; Caruso, R.; Monteleone, G. Role of IL-21 in inflammatory bowel disease. Expert Rev. Clin. Immunol. 2010, 6, 537–541. [Google Scholar] [CrossRef] [PubMed]
- Sarra, M.; Pallone, F.; Macdonald, T.T.; Monteleone, G. Targeting Interleukin-21 in Immune-Mediated Pathologies. Curr. Drug Targets 2010, 11, 645–649. [Google Scholar] [CrossRef] [PubMed]
- Monticelli, L.A.; Osborne, L.C.; Noti, M.; Tran, S.V.; Zaiss, D.M.W.; Artis, D. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin–EGFR interactions. Proc. Natl. Acad. Sci. USA 2015, 112, 10762–10767. [Google Scholar] [CrossRef] [Green Version]
- Duan, L.; Chen, J.; Zhang, H.; Yang, H.; Zhu, P.; Xiong, A.; Xia, Q.; Zheng, F.; Tan, Z.; Gong, F.; et al. Interleukin-33 ameliorates experimental colitis through promoting Th2/Foxp3+ regulatory T-cell responses in mice. Mol. Med. 2012, 18, 753–761. [Google Scholar] [CrossRef]
- Phuong, N.N.T.; Palmieri, V.; Adamczyk, A.; Klopfleisch, R.; Langhorst, J.; Hansen, W.; Westendorf, A.M.; Pastille, E. IL-33 Drives Expansion of Type 2 Innate Lymphoid Cells and Regulatory T Cells and Protects Mice From Severe, Acute Colitis. Front. Immunol. 2021, 12, 669787. [Google Scholar] [CrossRef]
- Seo, D.H.; Che, X.; Kwak, M.S.; Kim, S.; Kim, J.H.; Ma, H.W.; Kim, D.H.; Kim, T.I.; Kim, W.H.; Kim, S.W.; et al. Interleukin-33 regulates intestinal inflammation by modulating macrophages in inflammatory bowel disease. Sci Rep. 2017, 7, 851. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Waddell, A.; Vallance, J.; Moore, P.D.; Hummel, A.; Wu, D.; Shanmukhappa, S.K.; Fei, L.; Washington, M.K.; Minar, P.; Coburn, L.A.; et al. IL-33 Signaling Protects from Murine Oxazolone Colitis by Supporting Intestinal Epithelial Function. Inflamm. Bowel Dis. 2015, 21, 2737–2746. [Google Scholar] [CrossRef] [Green Version]
- Chen, J.; He, Y.; Tu, L.; Duan, L. Dual immune functions of IL-33 in inflammatory bowel disease. Histol. Histopathol. 2020, 35, 137–146. [Google Scholar]
- Sedhom, M.A.; Pichery, M.; Murdoch, J.R.; Foligné, B.; Ortega, N.; Normand, S.; Mertz, K.; Sanmugalingam, D.; Brault, L.; Grandjean, T.; et al. Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice. Gut 2013, 62, 1714–1723. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kobori, A.; Yagi, Y.; Imaeda, H.; Ban, H.; Bamba, S.; Tsujikawa, T.; Saito, Y.; Fujiyama, Y.; Andoh, A. Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J. Gastroenterol. 2010, 45, 999–1007. [Google Scholar] [CrossRef]
- Tahaghoghi-Hajghorbani, S.; Ajami, A.; Ghorbanalipoor, S.; Hosseini-Khah, Z.; Taghiloo, S.; Khaje-Enayati, P.; Hosseini, V. Protective effect of TSLP and IL-33 cytokines in ulcerative colitis. Autoimmun. Highlights 2019, 10, 1. [Google Scholar] [CrossRef] [PubMed]
- Sponheim, J.; Pollheimer, J.; Olsen, T.; Balogh, J.; Hammarström, C.; Loos, T.; Kasprzycka, M.; Sørensen, D.R.; Nilsen, H.R.; Küchler, A.M.; et al. Inflammatory Bowel Disease-Associated Interleukin-33 Is Preferentially Expressed in Ulceration-Associated Myofibroblasts. Am. J. Pathol. 2010, 177, 2804–2815. [Google Scholar] [CrossRef] [PubMed]
- Seidelin, J.B.; Bjerrum, J.T.; Coskun, M.; Widjaya, B.; Vainer, B.; Nielsen, O.H. IL-33 is upregulated in colonocytes of ulcerative colitis. Immunol. Lett. 2010, 128, 80–85. [Google Scholar] [CrossRef] [PubMed]
- Sun, M.; He, C.; Wu, W.; Zhou, G.; Liu, F.; Cong, Y.; Liu, Z. Hypoxia inducible factor-1α-induced interleukin-33 expression in intestinal epithelia contributes to mucosal homeostasis in inflammatory bowel disease. Clin. Exp. Immunol. 2016, 187, 428–440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bonilla, W.V.; Fröhlich, A.; Senn, K.; Kallert, S.; Fernandez, M.; Johnson, S.; Kreutzfeldt, M.; Hegazy, A.N.; Schrick, C.; Fallon, P.G.; et al. The Alarmin Interleukin-33 Drives Protective Antiviral CD8 + T Cell Responses. Science 2012, 335, 984–989. [Google Scholar] [CrossRef]
- Fonseca-Camarillo, G.; Furuzawa-Carballeda, J.; Granados, J.; Yamamoto-Furusho, J.K. Expression of interleukin (IL)-19 and IL-24 in inflammatory bowel disease patients: A cross-sectional study. Clin. Exp. Immunol. 2014, 177, 64–75. [Google Scholar] [CrossRef]
Disease | Classification | Frequency | Percent |
---|---|---|---|
UC | S1 | 16 | 32.7 |
S2 | 15 | 30.6 | |
S3 | 18 | 36.7 | |
Total | 49 | 100.0 | |
E1 | 5 | 10.2 | |
E2 | 24 | 49.0 | |
E3 | 20 | 40.8 | |
Total | 49 | 100.0 | |
CD | A1 | 1 | 1.4 |
A2 | 33 | 45.8 | |
A3 | 38 | 52.8 | |
Total | 72 | 100.0 | |
L1 | 26 | 36.1 | |
L2 | 14 | 19.4 | |
L3 | 30 | 41.7 | |
L3 + L4 | 2 | 2.8 | |
Total | 72 | 100.0 | |
B1 | 47 | 65.3 | |
B2 | 19 | 26.4 | |
B3 | 6 | 8.3 | |
Total | 72 | 100.0 |
Type of Disease | Type of Treatment | Frequency | Percentage | Valid Percent |
---|---|---|---|---|
UC | ADA | 1 | 2.0 | 5.3 |
IFX | 14 | 28.6 | 73.7 | |
USK | 1 | 2.0 | 5.3 | |
VDZ | 3 | 6.1 | 15.8 | |
Total | 19 | 38.8 | 100.0 | |
Other | 30 | 61.2 | ||
Total | 49 | 100.0 | ||
CD | ADA | 11 | 15.3 | 21.2 |
IFX | 33 | 45.8 | 63.5 | |
USK | 6 | 8.3 | 11.5 | |
VDZ | 2 | 2.8 | 3.8 | |
Total | 52 | 72.2 | 100.0 | |
Other | 20 | 27.8 | ||
Total | 72 | 100.0 |
Pre-Treatment | IL21 | IL33 | |||
---|---|---|---|---|---|
Patient Type | Stain Intensity | Frequency | Percent | Frequency | Percent |
IBD | 0 | 78 | 64.5 | 1 | 0.8 |
+ | 39 | 32.3 | 13 | 10.7 | |
++ | 4 | 3.3 | 69 | 57 | |
+++ | 0 | 0.0 | 38 | 31.4 | |
Total | - | 121 | 100.0 | 121 | 100.0 |
Controls | IL21 | IL33 | |||
0 | 17 | 85.0 | 8 | 40.0 | |
+ | 3 | 15.0 | 4 | 20.0 | |
++ | 0 | 0.0 | 2 | 10.0 | |
+++ | 0 | 0.0 | 6 | 30.0 | |
Total | - | 20 | 100 | 20 | 100 |
Post-Treatment | IL-21 | IL-33 | ||||
---|---|---|---|---|---|---|
Type of Treatment | Type of Biologic | Stain Intensity | Frequency | Percent | Frequency | Percent |
Biologics | Anti-TNFa | 0 | 57 | 80.3 | 0 | 0.0 |
+ | 12 | 16.9 | 5 | 7.0 | ||
++ | 1 | 1.4 | 22 | 31.0 | ||
+++ | 1 | 1.4 | 44 | 62.0 | ||
Total-Anti-TNFa | 71 | 100.0 | 71 | 100.0 | ||
USK | 0 | 5 | 71.4 | 0 | 0.0 | |
+ | 2 | 28.6 | 1 | 14.3 | ||
++ | 0 | 0.0 | 2 | 28.6 | ||
+++ | 0 | 0.0 | 4 | 57.1 | ||
Total-USK | 7 | 9.9 | 7 | 100.0 | ||
VDZ | 0 | 3 | 60.0 | 0 | 0.0 | |
+ | 2 | 40.0 | 0 | 0.0 | ||
++ | 0 | 0.0 | 3 | 60.0 | ||
+++ | 0 | 0.0 | 2 | 40.0 | ||
Total_VDZ | 5 | 100.0 | 5 | 100.0 | ||
Total-Biologics | 71 | - | 71 | - | ||
Non-Biologic Treatment | 0 | 37 | 74.0 | 1 | 2 | |
+ | 13 | 26.0 | 1 | 2 | ||
++ | 0 | 0.0 | 25 | 50.0 | ||
+++ | 0 | 0.0 | 23 | 46.0 | ||
Total-Non-Biologics | 50 | 100.0 | 50 | 100.0 |
Disease | Method | NR of Patients | IL-21 | IL-33 |
---|---|---|---|---|
IBD | IHC | 121 | No correlation was found between IL-21 and disease activity or phenotype. | 1. Significant increase in IL-33 expression in IBD patients vs. controls (p < 0.05). |
2. Significant increase in post-treatment IL-33 in the biologic group (p < 0.05). | ||||
3.Significant correlation between post-treatment IL-33 and score reduction in the USK-treated subgroup (p < 0.05). | ||||
UC | IHC | 49 | An increased IL-21 expression was found in UC group vs. controls but was not statistically significant. | 1. Significant increase in IL-33 expression in UC group vs. controls (p < 0.05). |
2. Significant increase in post-treatment IL-33 expression in the biologics group (p < 0.05). | ||||
3.Significant increase in post-treatment IL-33 expression in the anti-TNFa group (p < 0.001). | ||||
CD | IHC | 72 | An increased IL-21 expression was found in CD group vs. controls but was not statistically significant. | 1. Significant increase in IL-33 expression in CD group vs. controls (p < 0.05). |
2. Significant increase in post-treatment IL-33 expression in the biologics group/subgroups (p < 0.05). |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Toskas, A.; Milias, S.; Delis, G.; Meditskou, S.; Sioga, A.; Papamitsou, T. Expression of IL-21 and IL-33 in Intestinal Mucosa of Inflammatory Bowel Disease: An Immunohistochemical Study. Diagnostics 2023, 13, 2185. https://doi.org/10.3390/diagnostics13132185
Toskas A, Milias S, Delis G, Meditskou S, Sioga A, Papamitsou T. Expression of IL-21 and IL-33 in Intestinal Mucosa of Inflammatory Bowel Disease: An Immunohistochemical Study. Diagnostics. 2023; 13(13):2185. https://doi.org/10.3390/diagnostics13132185
Chicago/Turabian StyleToskas, Alexandros, Stefanos Milias, Georgios Delis, Soultana Meditskou, Antonia Sioga, and Theodora Papamitsou. 2023. "Expression of IL-21 and IL-33 in Intestinal Mucosa of Inflammatory Bowel Disease: An Immunohistochemical Study" Diagnostics 13, no. 13: 2185. https://doi.org/10.3390/diagnostics13132185