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Impaired immune and acute-phase responses in interleukin-6-deficient mice
Abstract
Interleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune response, acute-phase reaction and haematopoiesis (for reviews see refs 1, 2). In vitro, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and interleukin-11 display overlapping activities with IL-6. This functional redundancy may be explained by the interactions of specific binding receptors with a common signal-transducing receptor (gp130) (for reviews see refs 3, 4). To elucidate the unique function of IL-6 in vivo, we have disrupted the IL-6 gene by homologous recombination. IL-6-deficient mice develop normally. They fail to control efficiently vaccinia virus and infection with Listeria monocytogenes, a facultative intracellular bacterium. The T-cell-dependent antibody response against vesicular stomatitis virus is impaired. Further, the inflammatory acute-phase response after tissue damage or infection is severely compromised, whereas it is only moderately affected after challenge with lipopolysaccharide. We conclude that IL-6 production induced by injury or infection is an important in vivo SOS signal which coordinates activities of liver cells, macrophages and lymphocytes.
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“On the other hand, a certain amount of IL-6 is required for efficient immune defense (Kopf et al., 1994) and liver regeneration (Cressman et al., 1996; Sakamoto et al., 1999; Zimmers et al., 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 Kopf et al., 1994
In the citing paper
“IL-6 is a critical inducer of the acute phase (AP) response in the liver, 11”
From Interleukin 6 Is Important for Survival After Partial Hepatectomy in Mice (2003) · cites this paper as [11]
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“IL-6 transgenic mice show severe plasmacytosis with hypergammaglobulinemia (147), while IL-6-deficient mice are defective in immunoglobulin production (148, 149).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [148]
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Ahuja, P., Sdek, P., & MacLellan, W. R. (2007) · Physiological Reviews · doi:10.1152/physrev.00032.2006 · Cited by 568
Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients
Bologa, R. M., Levine, D., Ts, P., Cheigh, J. S., Serur, D. S., Kh, S., & Rubin, A. L. (1998) · American Journal of Kidney Diseases · doi:10.1053/ajkd.1998.v32.pm9669431 · Cited by 551
Shiloh, M. U., MacMicking, J. D., Nicholson, S., Brause, J. E., Potter, S. H., Marino, M., Fang, F. C., Dinauer, M. C., & Nathan, C. (1999) · Immunity · doi:10.1016/s1074-7613(00)80004-7 · Cited by 507
Interleukin-6: discovery of a pleiotropic cytokine.
Kishimoto, T. (2006) · Arthritis Research & Therapy · doi:10.1186/ar1916 · Cited by 497
“A study conducted in an IL-6 knockout mouse model [9] revealed that, compared with wild type, the antiviral antibody response was inhibited by more than 90% following immunization with a vesicular stomatitis virus.”
BackgroundSelf-citationInterleukin-6 in the Injured Patient
Biffl, W. L., Moore, E. E., Moore, F. A., & Peterson, V. M. (1996) · Annals of Surgery · doi:10.1097/00000658-199611000-00009 · Cited by 502
Pleiotropy and specificity: insights from the interleukin 6 family of cytokines
Murakami, M., Kamimura, D., & Hirano, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.027 · Cited by 533
Defective inflammatory response in interleukin 6-deficient mice.
Fattori, E., Cappelletti, M., Costa, P., Sellitto, C., Cantoni, L., Carelli, M., Faggioni, R., Fantuzzi, G., Ghezzi, P., & Poli, V (1994) · The Journal of experimental medicine · doi:10.1084/jem.180.4.1243 · Cited by 525
Targeting IL-6 trans-signalling: past, present and future prospects
Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M., & Scheller, J. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00856-y · Cited by 524
“Studies in IL-6-deficient mice showed that IL-6 contributes to the pathogenesis of many inflammatory diseases, including bacterial and viral infections 66 , arthritis 67,68 , experimental colitis 69 and multiple sclerosis 70 .”
Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update
Su, H., Lei, C., & Zhang, C. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00405 · Cited by 554
Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury.
Agaisse, H., Petersen, U., Boutros, M., Mathey-Prevot, B., & Perrimon, N. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00244-2 · Cited by 498
“response (Fattori et al., 1994; Kopf et al., 1994).”
The Role of Interleukin 6 During Viral Infections
Velázquez-Salinas, L., Verdugo-Rodríguez, A., Rodriguez, L. L., & Borca, M. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01057 · Cited by 488
Development and Selection of T Cells: Facts and Puzzles
Kisielow, P., & von Boehmer, H. (1995) · Advances in immunology · doi:10.1016/s0065-2776(08)60620-3 · Cited by 433
Samoilova, E. B., Horton, J. L., Hilliard, B. A., Liu, T.-S. T., & Chen, Y. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.12.6480 · Cited by 441
“Our observation that polyclonal T cell activation is normal in IL-6-deficient mice confirms earlier reports that immune response to mitogens in IL-6-deficient mice is comparable to that of normal mice (19, 20).”
BackgroundMethodResultInfluentialSack, G. H. (2018) · Molecular Medicine · doi:10.1186/s10020-018-0047-0 · Cited by 526
“Mice deficient in IL-6 can produce at least a partial APR, depending on the stimulus (Kopf et al. 1994).”
BackgroundTebbutt, N. C., Giraud, A. S., Inglese, M., Jenkins, B., Waring, P., Clay, F. J., Malki, S., Alderman, B. M., Grail, D., Hollande, F., et al. (2002) · Nature Medicine · doi:10.1038/nm763 · Cited by 474
“We detected no gastric hyperplasia in age-matched gp130 ΔSTAT , IL-6 −/− (ref”
BackgroundThe role of interleukin-6 in mucosal IgA antibody responses in vivo
Ramsay, A. J., Husband, A. J., Ramshaw, L. A., Bao, S., Matthaei, K. I., Koehler, G., & Kopf, M. (1994) · Science · doi:10.1126/science.8160012 · Cited by 454
Self-citationImpaired cutaneous wound healing in interleukin‐6‐deficient and immunosuppressed mice
Gallucci, R. M., Simeonova, P. P., Matheson, J. M., Kommineni, C., Guriel, J. L., Sugawara, T., & Luster, M. I. (2000) · The FASEB Journal · doi:10.1096/fj.00-0073com · Cited by 405
Marrack, P., & Kappler, J. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104554 · Cited by 439
Inhibition of Th1 Differentiation by IL-6 Is Mediated by SOCS1
Diehl, S. A., Anguíta, J., Hoffmeyer, A., Zapton, T., Ihle, J. N., Fikrig, E., & Rincón, M. (2000) · Immunity · doi:10.1016/s1074-7613(00)00078-9 · Cited by 402
The Immunobiology of the Interleukin-12 Family: Room for Discovery
Wojno, E. D. T., Hunter, C. A., & Stumhofer, J. S. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.011 · Cited by 496
“The generation of mice deficient in IL-6 affirmed its important role as an acute phase reactant and in innate resistance to bacterial challenges (Kopf et al., 1994).”
Camargo, C. A., Madden, J. F., Gao, W., Selvan, R. S., & Clavien, P. (1997) · Hepatology · doi:10.1002/hep.510260619 · Cited by 420
NF-κB and Rel Proteins in Innate Immunity
Kopp, E. B., & Ghosh, S. (1995) · Advances in immunology · doi:10.1016/s0065-2776(08)60618-5 · Cited by 423
The role of IL-6 in host defence against infections: immunobiology and clinical implications
Rose-John, S., Winthrop, K., & Calabrese, L. (2017) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2017.83 · Cited by 424
Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis
Ancrile, B., Lim, K.-H., & Counter, C. M. (2007) · Genes & Development · doi:10.1101/gad.1549407 · Cited by 422
“129S2-IL6tm1Kopf/J) (Kopf et al. 1994) (Jackson Laboratory) were shaved, and the following day, 150 µL of 125 µg/mL DMBA (Sigma) in DMSO were applied topically, followed 1 wk later by twice-weekly topical applications of 150 µL of 10−4 M TPA (Sigma) in DMSO for 20 wk.”
MethodInterleukin 6 plays a key role in the development of antigen-induced arthritis
Ohshima, S., Saeki, Y., Mima, T., Sasai, M., Nishioka, K., Nomura, S., Kopf, M., Katada, Y., Tanaka, T., Suemura, M., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.8222 · Cited by 406
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Tofaris, G., Patterson, P., Jessen, K., & Mirsky, R. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-15-06696.2002 · Cited by 403
“The IL -6 knock-out strain (il-6/) was produced by Kopf et al. (1994) and was purchased from The Jackson Laboratory (Bar Harbor, M A.) Sciatic nerves were excised from wild-type, lif/, il- 6/, as well as LI F/ IL -6 double knock-out (lif/il-6/) mice.”
MethodGlucocorticoids and immune function: unknown dimensions and new frontiers
Wilckens, T., & de Rijk, R. (1997) · Immunology Today · doi:10.1016/s0167-5699(97)01111-0 · Cited by 350
Aliyu, M., Zohora, F. T., Anka, A. U., Ali, K., Maleknia, S., Saffarioun, M., & Azizi, G. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109130 · Cited by 455
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New Insights into the Biology of the Acute Phase Response
Suffredini, A. F., Fantuzzi, G., Badolato, R., Oppenheim, J. J., & O’Grady, N. P. (1999) · Journal of Clinical Immunology · doi:10.1023/a:1020563913045 · Cited by 397
“A critical role for IL-6 in the acute phase response is seen in the IL-6 knockout mouse, which has significant depression of acute phase protein release compared to normal mice in response to sterile inflammation with turpentine and intracellular Gram-positive infection, and less so with LPS (12).”
BackgroundMedium-chain Fatty Acids as Ligands for Orphan G Protein-coupled Receptor GPR84
Wang, J., Wu, X., Simonavicius, N., Tian, H., & Ling, L. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608019200 · Cited by 431
Metadata
- Authors
- Kopf, M., Baumann, H., Freer, G., Freudenberg, M., Lamers, M., Kishimoto, T., Zinkernagel, R., Bluethmann, H., & Köhler, G.
- Affiliations
- University of Zurich (CH)
- Max Planck Society (DE)
- The University of Osaka (JP)
- F. Hoffmann-La Roche AG (CH)
- Roswell Park Comprehensive Cancer Center (US)
- Venue
- Nature
- Published
- 1994-03-24
- Volume
- 368
- Issue
- 6469
- Pages
- 339-342
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2067761476
- Cited by
- 1,768
- References
- 0
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 23 · 2023: 36 · 2022: 44 · 2021: 58 · 2020: 43 · 2019: 52 · 2018: 46 · 2017: 60 · 2016: 57 · 2015: 44 · 2014: 48 · 2013: 56 · 2012: 64
- FWCI
- 28.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- interleukin-6, IL-6-deficient mice, gene disruption, acute phase response, immune response, vaccinia virus infection, Listeria monocytogenes, T cell-dependent antibody response, vesicular stomatitis virus, lipopolysaccharide, gp130, cytokine redundancy, inflammation, macrophages, liver
- MeSH terms
- Acute-Phase Reaction, Animals, B-Lymphocytes, Immunity, Listeriosis, Lymphoid Tissue, Mice, Inbred C57BL, RNA, Messenger, T-Lymphocytes, Vesicular stomatitis Indiana virus, Interleukin-6, Rhabdoviridae Infections, Mice
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