IL-6 and Crohns Disease
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine with central roles in immune regulation, inflammation, hematopoiesis, and oncogenesis. Its biological activities are shared by IL-6-family of cytokines such as leukemia inhibitory factor and oncostatin M. When IL-6 binds to IL-6R, the IL-6/IL-6R complex then associates with gp130, the common signal transducer of cytokines related to IL-6. IL-6R does not have to be expressed on the cell surface for IL-6 signaling because soluble form of IL-6R (sIL-6R) can bind to IL-6 and function through gp130. Increased levels of IL-6 and sIL-6R have been demonstrated in both serum and intestinal tissues of the patients with active Crohn's disease. In animal model studies, anti-IL-6R monoclonal antibody (mAb) successfully prevented intestinal inflammation and systemic wasting disease by suppressing adhesion molecule expression by vascular endothelium. It also reduced colonic expression of tumor necrosis factor alpha, IL-1beta, and interferon gamma mRNA without affecting the production of transforming growth factor beta, IL-10, and IL-4. Moreover, the treatment displayed therapeutic efficacy against established colitis through the induction of lamina propria T-cell apoptosis. These results strongly suggest that specific targeting of IL-6/sIL-6R pathway will be a promising new approach for the treatment of Crohn's disease, and the clinical trial of humanized anti-IL-6R mAb has been carried out.
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Increased IL-6 activity is associated with chronic inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and Crohn's disease.
“Increased activity of interleukin (IL)-6 has been associated with chronic inflammatory diseases including rheumatoid arthritis (Hirano et al., 1988), multiple sclerosis (Frei et al., 1991; Navikas et al., 1996), and Crohn's disease (Ito, 2003).”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Ito, 2003
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Il-6 signaling in inflammatory bowel disease: Pathophysiological role and clinical relevance
Mudter, J., & Neurath, M. F. (2007) · Inflammatory Bowel Diseases · doi:10.1002/ibd.20148 · Cited by 438 · see citing works
Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease
O’Sullivan, L. A., Liongue, C., Lewis, R. S., Stephenson, S. E. M., & Ward, A. C. (2007) · Molecular Immunology · doi:10.1016/j.molimm.2006.11.025 · Cited by 308 · see citing works
Cellular and molecular mechanisms of intestinal fibrosis
Speca, S. (2012) · World Journal of Gastroenterology · doi:10.3748/wjg.v18.i28.3635 · Cited by 272 · see citing works
Cellular and Molecular Mediators of Intestinal Fibrosis
Lawrance, I. C., Rogler, G., Bamias, G., Breynaert, C. M., Florholmen, J. R., Pellino, G., Reif, S. S., Speca, S., & Latella, G. (2014) · Journal of Crohn s and Colitis · doi:10.1016/j.crohns.2014.09.008 · Cited by 176 · see citing works
Latella, G., Rogler, G., Bamias, G., Breynaert, C. M., Florholmen, J., Pellino, G., Reif, S. S., Speca, S., & Lawrance, I. C. (2014) · Journal of Crohn s and Colitis · doi:10.1016/j.crohns.2014.03.008 · Cited by 165 · see citing works
Lee, J. Y., & Park, W. (2011) · Molecules · doi:10.3390/molecules16087132 · Cited by 137 · see citing works
Apoptosis of T cells and the control of inflammatory bowel disease: therapeutic implications
Mudter, J., & Neurath, M. F. (2006) · Gut · doi:10.1136/gut.2005.090464 · Cited by 123 · see citing works
Interleukin-6 trans-signaling in inflammatory bowel disease.
Mitsuyama, K., Sata, M., & Rose-John, S. (2006) · Cytokine & growth factor reviews · doi:10.1016/j.cytogfr.2006.09.003 · Cited by 122 · see citing works
Effect of particulate bioactive glasses on human macrophages and monocytes in vitro
Day, R. M., & Boccaccini, A. R. (2005) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.30262 · Cited by 105 · see citing works
Can we prevent, reduce or reverse intestinal fibrosis in IBD?
Latella, G., Sferra, R., Speca, S., Vetuschi, A., & Gaudio, E. (2013) · PubMed · Cited by 97 · see citing works
Song, J., Matsuda, C., Kai, Y., Nishida, T., Nakajima, K., Mizushima, T., Kinoshita, M., Yasue, T., Sawa, Y., & Ito, T. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.119172 · Cited by 97 · see citing works
Liang, Z., Wu, G., Fan, C., Xu, J., Jiang, S., Yan, X., Di, S., Ma, Z., Hu, W., & Yang, Y. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.11.001 · Cited by 92 · see citing works
Bettenworth, D., & Rieder, F. (2014) · Fibrogenesis & Tissue Repair · doi:10.1186/1755-1536-7-5 · Cited by 80 · see citing works
Scharl, M. M., Hruz, P. L., & McCole, D. F. (2010) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21325 · Cited by 75 · see citing works
Abad, C., Juarranz, Y., Martínez, C., Arranz, A., Rosignoli, F., García-Gómez, M., Leceta, J., & Gomariz, R. P. (2005) · Inflammatory Bowel Diseases · doi:10.1097/01.mib.0000171872.70738.58 · Cited by 67 · see citing works
Th1 shift in CIDP versus Th2 shift in vasculitic neuropathy in CSF
Mei, F.-J., Ishizu, T., Murai, H., Osoegawa, M., Minohara, M., Kun-nan, Z., & Kira, J. (2004) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.10.001 · Cited by 55 · see citing works
Ramírez, K., Huerta, R., Oswald, É., García-Tovar, C. G., Hernandez, J. M., & Navarro‐García, F. (2004) · Infection and Immunity · doi:10.1128/iai.73.1.103-113.2005 · Cited by 38 · see citing works
Pattanshetty, D. J., Anna, K., Gajulapalli, R. D., & Sappati-Biyyani, R. (2015) · Saudi Journal of Gastroenterology · doi:10.4103/1319-3767.166208 · Cited by 36 · see citing works
Nishizawa, M., Yamamoto, H., Imagawa, H., Barbier-Chassefière, V., Petit, E., Azuma, I., & Papy-García, D. (2007) · The Journal of Organic Chemistry · doi:10.1021/jo062018j · Cited by 36 · see citing works
Sun, X., Wen, K., Xu, Z., He, Z., Wu, B., Yang, X., & Wang, X. (2020) · Chinese Medicine · doi:10.1186/s13020-019-0282-5 · Cited by 32 · see citing works
Mohan, M., Aye, P. P., Borda, J. T., Alvarez, X. A., & Lackner, A. A. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070017 · Cited by 32 · see citing works
Møller, P. L., Pærregaard, A., Gad, M., Kristensen, N. N., & Claësson, M. H. (2005) · Inflammatory Bowel Diseases · doi:10.1097/01.mib.0000175906.77340.15 · Cited by 32 · see citing works
Bianchi, E., Taurone, S., Bardella, L., Signore, A., Pompili, E., Sessa, V., Chiappetta, C., Fumagalli, L., Gioia, C. R. T. D., Pastore, F. S., et al. (2015) · Clinical Science · doi:10.1042/cs20150088 · Cited by 30 · see citing works
Sobotta, S., Raue, A., Huang, X., Vanlier, J., Jünger, A., Bohl, S., Albrecht, U., Hahnel, M. J., Wolf, S., Mueller, N. S., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00775 · Cited by 28 · see citing works
“Increased activity of interleukin (IL)-6 has been associated with chronic inflammatory diseases including rheumatoid arthritis (Hirano et al., 1988), multiple sclerosis (Frei et al., 1991; Navikas et al., 1996), and Crohn’s disease (Ito, 2003).”
BackgroundLahdou, I., Sadeghi, M., Oweira, H., Fusch, G., Daniel, V., Mehrabi, A., Jung, G., Elhadedy, H., Schmidt, J., Șandra-Petrescu, F., et al. (2012) · Human Immunology · doi:10.1016/j.humimm.2012.09.009 · Cited by 28 · see citing works
Dekita, M., Wu, Z., Ni, J., Zhang, X., Liu, Y., Yan, X., Nakanishi, H., & Takahashi, I. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00470 · Cited by 26 · see citing works
Singh, B. P., Marshall, J. L., & He, A. R. (2019) · The Oncologist · doi:10.1634/theoncologist.2018-0304 · Cited by 26 · see citing works
Dittmer, A., & Dittmer, J. (2022) · Cancers · doi:10.3390/cancers14204983 · Cited by 24 · see citing works
Proinflammatory Cytokines and Signaling Pathways in Intestinal Innate Immune Cells
Sartor, R. B., & Hoentjen, F. (2005) · Elsevier eBooks · doi:10.1016/b978-012491543-5/50039-5 · Cited by 24 · see citing works
Andriano, T. M., Benesh, G., Babbush, K. M., Hosgood, H. D., Lin, J., & Cohen, S. R. (2022) · International Journal of Dermatology · doi:10.1111/ijd.16244 · Cited by 23 · see citing works
Eder, P., Łykowska‐Szuber, L., Krela‐Kaźmierczak, I., Stawczyk‐Eder, K., Zabel, M., & Linke, K. (2012) · Journal of Crohn s and Colitis · doi:10.1016/j.crohns.2012.09.006 · Cited by 22 · see citing works
Sadeghi, M., Daniel, V., Naujokat, C., Mehrabi, A., & Opelz, G. (2006) · Transplantation · doi:10.1097/01.tp.0000226076.04938.98 · Cited by 21 · see citing works
Gallucci, R. M., Sloan, D. K., O'Dell, S. J., & Reinke, L. A. (2004) · Alcoholism Clinical and Experimental Research · doi:10.1097/01.alc.0000118316.20560.0d · Cited by 21 · see citing works
Mohan, M., Aye, P. P., Borda, J. T., Alvarez, X. A., & Lackner, A. A. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.080108 · Cited by 20 · see citing works
Seo, M. J. (2013) · Journal of Microbiology and Biotechnology · doi:10.4014/jmb.1211.11032 · Cited by 19 · see citing works
Fibrogenesis and fibrosis in inflammatory bowel diseases: Good and bad side of same coin?
Principi, M. (2013) · World Journal of Gastrointestinal Pathophysiology · doi:10.4291/wjgp.v4.i4.100 · Cited by 18 · see citing works
Cammisa, I., Rigante, D., & Cipolla, C. (2025) · Children · doi:10.3390/children12040495 · Cited by 17 · see citing works
Li, C., Shoji, S., & BEEBE, J. S. (2018) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13641 · Cited by 16 · see citing works
Homocysteine Promotes Intestinal Fibrosis in Rats with Trinitrobenzene Sulfonic Acid-Induced Colitis
Ding, H., Gan, H., Fan, W.-J., Cao, L., Xu, J.-M., & Mei, Q. (2014) · Digestive Diseases and Sciences · doi:10.1007/s10620-014-3379-9 · Cited by 15 · see citing works
Disturbances in apoptosis of lamina propria lymphocytes in Crohn’s disease
Eder, P., Łykowska‐Szuber, L., Krela‐Kaźmierczak, I., Stawczyk‐Eder, K., Iwanik, K., Majewski, P., Sterzyńska, K., Zabel, M., & Linke, K. (2015) · Archives of Medical Science · doi:10.5114/aoms.2015.54203 · Cited by 13 · see citing works
Tran, M. T. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1376123 · Cited by 11 · see citing works
Klein, C., Medina, E., Sander, L., Dierssen, U., Roskams, T., Mueller, W., Trautwein, C., & Goldmann, O. (2007) · The Journal of Infectious Diseases · doi:10.1086/520090 · Cited by 11 · see citing works
Role of IRF4-Mediated Inflammation: Implication in Neurodegenerative Diseases
Liu, F. (2017) · Neurology & Neurotherapy Open Access Journal · doi:10.23880/nnoaj-16000107 · Cited by 5 · see citing works
Yu, Z., Liu, W., Liu, D., & Fan, L. (2006) · Cellular Immunology · doi:10.1016/j.cellimm.2006.07.008 · Cited by 7 · see citing works
Eder, P., Łykowska‐Szuber, L., Stawczyk‐Eder, K., Krela‐Kaźmierczak, I., & Linke, K. (2014) · Gastroenterology Review · doi:10.5114/pg.2014.46162 · Cited by 7 · see citing works
Dubey, P., Shi, T., Coltharp, M., & Reddy, S. (2022) · Dietetics · doi:10.3390/dietetics1020008 · Cited by 7 · see citing works
Scheller, J., Kovaleva, M., Rabe, B., Eichler, J., Kallen, K., & Rose‐John, S. (2004) · Journal of Immunological Methods · doi:10.1016/j.jim.2004.05.002 · Cited by 7 · see citing works
Ezaouine, A., Salam, M. R., Nouadi, B., Anachad, O., Messal, M. E., Chegdani, F., & Bennis, F. (2022) · Bioinformatics and Biology Insights · doi:10.1177/11779322221115665 · Cited by 6 · see citing works
Bilsborough, J., & Viney, J. L. (2006) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.1.1.69 · Cited by 6 · see citing works
Augustyniak, D., Majkowska-Skrobek, G., Basiewicz-Worsztynowicz, B., & Jankowski, A. (2006) · PubMed · Cited by 6 · see citing works
Eder, P., Łykowska‐Szuber, L., Krela‐Kaźmierczak, I., Stawczyk‐Eder, K., Sterzyńska, K., Iwanik, K., Majewski, P., Zabel, M., & Linke, K. (2013) · Folia Histochemica et Cytobiologica · doi:10.5603/fhc.2013.0034 · Cited by 4 · see citing works
Efficacy of thalidomide on trinitrobenzene sulfonate-induced colitis in young rats and its mechanism
Xu, J., Zheng, C., Huang, Y., & Liang, Y. (2014) · Chinese Medical Journal · doi:10.3760/cma.j.issn.0366-6999.20133290 · Cited by 3 · see citing works
Traditional Chinese Medicine: A Promising Treatment Option for Intestinal Fibrosis
Zhou, M., Chen, Y., Jin, W., Li, P., Hu, J., & Guo, X. (2024) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x24500812 · Cited by 2 · see citing works
Wang, X., Gu, X. R., & Liu, F. (2023) · Personalized Medicine · doi:10.2217/pme-2023-0089 · Cited by 1 · see citing works
Ulhaq, Z. S., Zulkarnain, Z., Istifiani, L. A., Pamungkas, S. A., Susiati, Soeatmadji, D. W., & Aulanni’am, A. (2025) · Endocrinología Diabetes y Nutrición (English ed ) · doi:10.1016/j.endien.2025.501598 · Cited by 1 · see citing works
Application of IL-6 antagonists in autoimmune disorders
Borges, T., Barbosa, A., & Silva, S. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-824390-9.00002-5 · Cited by 1 · see citing works
Ulhaq, Z. S., Zulkarnain, Z., Istifiani, L. A., Pamungkas, S. A., Susiati, Soeatmadji, D. W., & Aulanni’am, A. (2025) · Endocrinología Diabetes y Nutrición · doi:10.1016/j.endinu.2025.501598 · Cited by 1 · see citing works
Eder, P. (2012) · Biblioteka Uniwersytetu Medycznego w Poznaniu
Preclinical Approaches for the Safety Assessment of Cytokines
Thomas, P. T., & Beck‐Westermeyer, M. S. (2007) · Methods in pharmacology and toxicology · doi:10.1007/978-1-59745-350-9_9
New Non-anti-TNF-α Biological Therapies for the Treatment of Inflammatory Bowel Disease
Rashid, F., & Lichtenstein, G. R. (2017) · Springer eBooks · doi:10.1007/978-3-319-49215-5_35
New Non-anti-TNF-α Biological Therapies for the Treatment of Inflammatory Bowel Disease
Rao, B. B., Bhattacharya, A., & Lichtenstein, G. R. (2023) · Springer eBooks · doi:10.1007/978-3-031-14744-9_34
Ca2 + influx channel inhibitor SARAF protects rats from severe acute pancreatitis induced colonitis
Liu, Y., Cao, J., & Liu, H. (2026) · 3 Biotech · doi:10.1007/s13205-025-04687-7
Nanoengineered RNA delivery systems for gene therapy in intestinal fibrosis
Ferreira, B., Teixeira, N., & Sarmento, B. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115242
Othman, A. A., & Hameed, W. S. (2026) · Journal of Genetic Engineering and Biotechnology · doi:10.1016/j.jgeb.2026.100798
Liu, D., Zuo, H., Wang, Y., 葛学翠, & Zhang, C. (2026) · Journal of Radiation Research and Applied Sciences · doi:10.1016/j.jrras.2026.102718
- Authors
- Ito, H.
- Affiliations
- The University of Osaka (JP)
- Corresponding author
- Ito, Hiroaki
- ORCID
- Ito, Hiroaki
- Venue
- Current Drug Target -Inflammation & Allergy
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2003-06-01
- Volume
- 2
- Issue
- 2
- Pages
- 125-130
- ISSN
- 1568-010X (ISSN-L)
- OpenAlex
- W2022502525
- Cited by
- 65
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 5 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 4 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 4
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Drug Targets - Inflammation & Allergy (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- interleukin-6, Crohn's disease, soluble IL-6 receptor, gp130 signaling, humanized monoclonal antibody, intestinal inflammation, colitis, adhesion molecules, cytokine therapy
- MeSH terms
- Animals, Arthritis, Rheumatoid, Crohn Disease, Humans, Signal Transduction, Interleukin-6, Cytokines, Receptors, Interleukin-6
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