Disease-association analysis of an inflammation-related feedback loop
Open accessAbstract
The IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets.
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IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm.
“Among them, IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm (1, 3, 10–26).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [10]
The Introduction describes IL-6 as important in autoimmune diseases and other inflammatory conditions, and the Discussion links the IL-6 amplifier to chronic inflammation in humans. The passages do not support the additional claims about cancer or cytokine storm; searches for those terms found no relevant discussion in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe IL-6 amplifier plays a key role in inflammatory diseases including cytokine storm syndromes, autoimmune diseases and cancer.
“It too plays a key role in inflammatory diseases including cytokine storm syndromes, autoimmune diseases and cancer (10, 11, 15, 41, 66–68)”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [10]
The Discussion (page not specified) describes the IL-6 amplifier as important in chronic inflammation and reports associations with autoimmune diseases, including rheumatoid arthritis and lupus. The passages found do not support the added claims about cytokine storm syndromes or cancer. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEnhanced production of epiregulin and TNFα is induced by activation of the IL-6 Amp, and these molecules further activate NF-κB alone or STAT3 as well.
“In addition, the enhanced production of epiregulin and TNFα is induced by the activation of the IL-6 Amp, and these molecules further activate NF-κB alone or STAT3 as well (10).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [10]
The Results report that epiregulin expression increases after IL-6 and IL-17 stimulation and that epiregulin enhances NF-κB activation through the PI3Kα pathway. The available passages do not support the parallel claims about TNFα production or TNFα activating NF-κB or STAT3; searches for TNF and tumor necrosis factor found no relevant passage. Page numbers were not provided. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTarget molecules of the IL-6 Amp include EGFR, c-Myc, Pim1, VEGFα, hypoxia-inducible factor 1-alpha, MMPs and many pro-inflammatory cytokines and growth factors involved in cell survival, proliferation, angiogenesis and metastasis.
“Target molecules of the IL-6 Amp include EGFR, c-Myc, Pim1, VEGFα, hypoxia-inducible factor 1-alpha (HIF1-α), MMPs and many pro-inflammatory cytokines and growth factors involved in cell survival, proliferation, angiogenesis and metastasis (Fig. 3) (10, 11).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [10]
The Results report that IL-6 stimulation increased ErbB1 (EGFR) expression, and the Discussion says IL-6 amplifier activation induces chemokines and pro-inflammatory cytokines. Our copy does not substantiate the listed c-Myc, Pim1, VEGFα, HIF1-α, or MMPs as amplifier targets, or the asserted roles in cell survival, proliferation, angiogenesis, and metastasis (searched those terms). (LLM, conf=0.87)
Experimental — accuracy not yet measured
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“, 2000), and Vegfa (Adachi et al., 2006; Rojo et al., 2004) were required for IL-6 amplifier activation according to our functional screening, suggesting a possible positive feedback mechanism of IL-6 amplifier activation through these molecules.”
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Self-citationAnimal models of arthritis caused by systemic alteration of the immune system.
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“Clinical Assessment of Arthritis Mice were inspected and assessed for signs of arthritis as described previously (Atsumi et al., 2002; Ishihara et al., 2004; Murakami et al., 2011; Ogura et al., 2008; Sawa et al., 2006).”
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BackgroundSearching for the missing heritability of complex diseases
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IL-6 in inflammation, autoimmunity and cancer
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“In addition, the enhanced production of epiregulin and TNF α is induced by the activation of the IL-6 Amp, and these molecules further activate NF-κ B alone or STAT3 as well (10).”
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“In addition, elevated Abbreviations: ACE2, angiotensin-converting enzyme II; AT1R, activation of angiotensin-1-receptor; ADAM17, metalloprotease 17; BLC, B-lymphocyte chemoattractant; BAFFR, B-cell activating factor receptor; CD40+, cluster of differentiation 40; COX-2, cyclooxygenase-2; CXCL, C-X-C- motif chemokine;…”
InfluentialNEDD4 Is Involved in Inflammation Development during Keloid Formation
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EBV-encoded RNA via TLR3 induces inflammation in nasopharyngeal carcinoma
Li, Z., Duan, Y., Cheng, S., Chen, Y., Hu, Y., Zhang, L., He, J., Liao, Q., Yang, L., & Sun, L. (2015) · Oncotarget · doi:10.18632/oncotarget.4552 · Cited by 67 · see citing works
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“Activation of the inflammation amplifier is associated with many human diseases and disorders such as autoimmune and neurodegenerative diseases including MS ( Murakami et al., 2013 ; Atsumi et al., 2014 ).”
BackgroundInfluentialSelf-citationInterleukin-6 in juvenile idiopathic arthritis
Akioka, S. (2019) · Modern Rheumatology · doi:10.1080/14397595.2019.1574697 · Cited by 57 · see citing works
“pathway [17] is known to act as an IL-6 amplifier in RA”
BackgroundMast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis
Nishida, K., Hasegawa, A., Yamasaki, S., Uchida, R., Ohashi, W., Kurashima, Y., Kunisawa, J., Kimura, S., Iwanaga, T., Watarai, H., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-47132-5 · Cited by 53 · see citing works
Self-citationTenophages: a novel macrophage-like tendon cell population expressing CX3CL1 and CX3CR1
Lehner, C., Spitzer, G., Gehwolf, R., Wagner, A., Weißenbacher, N., Deininger, C., Emmanuel, K., Wichlas, F., Tempfer, H., & Traweger, A. (2019) · Disease Models & Mechanisms · doi:10.1242/dmm.041384 · Cited by 50 · see citing works
Nakanishi, K., Nishida, M., Harada, M., Ohama, T., Kawada, N., Murakami, M., Moriyama, T., & Yamauchi‐Takihara, K. (2015) · Scientific Reports · doi:10.1038/srep14230 · Cited by 41 · see citing works
Self-citationRbm10 regulates inflammation development via alternative splicing of Dnmt3b
Atsumi, T., Suzuki, H., Jiang, J., Okuyama, Y., Nakagawa, I., Ota, M., Tanaka, Y., Ohki, T., Katsunuma, K., Nakajima, K., et al. (2017) · International Immunology · doi:10.1093/intimm/dxx067 · Cited by 41 · see citing works
Self-citationModulation of Pathological Pain by Epidermal Growth Factor Receptor
Borges, J. P., Mekhail, K., Fairn, G. D., Antonescu, C. N., & Steinberg, B. E. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.642820 · Cited by 37 · see citing works
“Reports first demonstrated that EREG may act synergistically with cytokines to propagate the inflammatory response as the ligand itself is expressed following in vitro stimulation with interleukin (IL)-6 and IL-17 (Murakami et al., 2013).”
BackgroundOta, M., Tanaka, Y., Nakagawa, I., Jiang, J.-J., Arima, Y., Kamimura, D., Onodera, T., Iwasaki, N., & Murakami, M. (2019) · Arthritis & Rheumatology · doi:10.1002/art.41182 · Cited by 28 · see citing works
Self-citationThe gateway theory: bridging neural and immune interactions in the CNS
Kamimura, D., Yamada, M., Harada, M., Sabharwal, L., Meng, J., Bando, H., Ogura, H., Atsumi, T., Arima, Y., & Murakami, M. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00204 · Cited by 35 · see citing works
Self-citationŠtofková, A., Kamimura, D., Ohki, T., Ota, M., Arima, Y., & Murakami, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-38895-y · Cited by 35 · see citing works
Self-citationDysregulation of placental ABC transporters in a murine model of malaria-induced preterm labor
Fontes, K. N., Reginatto, M. W., Silva, N. L., de Andrade, C. B. V., Bloise, F. F., Monteiro, V. R. D. S., Silva‐Filho, J. L., Império, G. E., Pimentel‐Coelho, P. M., Pinheiro, A. A. S., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-47865-3 · Cited by 35 · see citing works
Takada, Y., Kamimura, D., Jiang, J.-J., Higuchi, H., Iwami, D., Hotta, K., Tanaka, Y., Ota, M., Higuchi, M., Nishio, S., et al. (2020) · International Immunology · doi:10.1093/intimm/dxaa032 · Cited by 31 · see citing works
Self-citationSabharwal, L., Kamimura, D., Meng, J., Bando, H., Ogura, H., Nakayama, C., Jiang, J., Kumai, N., Suzuki, H., Atsumi, T., et al. (2014) · The Journal of Biochemistry · doi:10.1093/jb/mvu057 · Cited by 34 · see citing works
Self-citationThe NF-κB pathway: Key players in neurocognitive functions and related disorders
Yang, D., Su, J., Chen, Y., & Chen, G. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.177038 · Cited by 30 · see citing works
Revisiting the 1986 Molecular Cloning of Interleukin 6
Hirano, T. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00456 · Cited by 30 · see citing works
Self-citationIL-17A synergistically enhances TNFα-induced IL-6 and CCL20 production in 3T3-L1 adipocytes
Shinjo, T., Iwashita, M., Yamashita, A., Sano, T., Tsuruta, M., Matsunaga, H., Sanui, T., Asano, T., & Nishimura, F. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.06.049 · Cited by 29 · see citing works
An, L., & Yin, F. (2021) · Tissue and Cell · doi:10.1016/j.tice.2021.101669 · Cited by 29 · see citing works
Liu, Y., Zhang, Z., Han, D., Zhao, Y., Yan, X., & Cui, S. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.980987 · Cited by 30 · see citing works
The dichotomous role of epiregulin in pain
Verma, V., Khoury, S., Parisien, M., Cho, C., Maixner, W. D., Martin, L. J., & Diatchenko, L. B. (2020) · Pain · doi:10.1097/j.pain.0000000000001792 · Cited by 28 · see citing works
“EREG production may be necessary for the resolution of inflammation and the natural recovery from pain; however, EREG may trigger expression of signaling cascades in primary afferent nerves or in the dorsal horn that promote long-term changes in neuronal excitability.(15,30,32) Nevertheless, a full understanding of th…”
BackgroundHiguchi, H., Kamimura, D., Jiang, J., Atsumi, T., Iwami, D., Hotta, K., Harada, H., Takada, Y., Kanno‐Okada, H., Hatanaka, K. C., et al. (2020) · International Immunology · doi:10.1093/intimm/dxaa003 · Cited by 27 · see citing works
Self-citationBreakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II
Meng, J., Jiang, J.-J., Atsumi, T., Bando, H., Okuyama, Y., Sabharwal, L., Nakagawa, I., Higuchi, H., Ota, M., Okawara, M., et al. (2016) · Journal of Immunology · doi:10.4049/jimmunol.1601082 · Cited by 22 · see citing works
Self-citationCai, H., Chen, Y., Feng, Y., Asadi, M., Kaufman, L., Lee, K., Kehrer, T., Miorin, L., García‐Sastre, A., Gusella, G. L., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.12.008 · Cited by 26 · see citing works
Proliferative Pathways of Vascular Smooth Muscle Cells in Response to Intermittent Hypoxia
Kyotani, Y., Takasawa, S., & Yoshizumi, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112706 · Cited by 24 · see citing works
“demonstrated the involvement of epiregulin in the development of inflammatory diseases [91].”
BackgroundFatal cytokine release syndrome by an aberrant FLIP/STAT3 axis
Musiu, C., Caligola, S., Fiore, A., Lamolinara, A., Frusteri, C., Pizzo, F. D. D., Sanctis, F. D., Canè, S., Adamo, A., Hofer, F., et al. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00866-0 · Cited by 24 · see citing works
Cao, J., Yang, X., Xiong, L., Wu, M., Chen, S., Xu, H., Gong, Y., Zhang, L., Zhang, Q., & Zhang, X. L. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.990469 · Cited by 24 · see citing works
“The IL6 amplifier (IL6 Amp) is an amplification mechanism, the synergistic interaction of STAT3 with nuclear factor-κB (NF-κB) produces IL6 and various other cytokines and chemokines (Hirano, 2010; Murakami et al., 2013; Atsumi et al., 2014).”
BackgroundHuseby, E., Kamimura, D., Arima, Y., Parello, C. S. L., Sasaki, K., & Murakami, M. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00295 · Cited by 29 · see citing works
“Importantly, clinical symptoms of EAE, and several additional chronic inflammatory diseases, are significantly improved in mice unable to activate the inflammation amplifier (Ogura et al., 2008; Arima et al., 2012; Lee et al., 2012; Murakami et al., 2013; Harada et al., 2015).”
BackgroundSelf-citationTanaka, Y., Sabharwal, L., Ota, M., Nakagawa, I., Jiang, J.-J., Arima, Y., Ogura, H., Okochi, M., Ishii, M., Kamimura, D., et al. (2018) · Journal of Immunology · doi:10.4049/jimmunol.1701446 · Cited by 16 · see citing works
“Next, to investigate whether Psen1 acts as a positive regulator of the NF-kB pathway in vivo, we employed cytokine-induced arthritis in F759 mice (7, 13, 14, 16).”
BackgroundMethodInfluentialSelf-citationMartinelli, L. M., Reginatto, M. W., Fontes, K. N., de Andrade, C. B. V., Monteiro, V. R. D. S., Gomes, H. R., de Almeida, F. R. C. L., Bloise, F. F., Matthews, S. G., Ortiga-Carvalho, T. M., et al. (2020) · Reproductive Toxicology · doi:10.1016/j.reprotox.2020.09.001 · Cited by 21 · see citing works
STAT3 Activation Correlates with Adventitial Neutrophil Infiltration in Human Aortic Dissection
Yoshida, S., Yamamoto, M., Aoki, H., Fukuda, H., Akasu, K., Takagi, K., Shojima, T., Fukumoto, Y., Akashi, H., & Tanaka, H. (2019) · Annals of Vascular Diseases · doi:10.3400/avd.oa.19-00007 · Cited by 22 · see citing works
Reginatto, M., Fontes, K. N., Monteiro, V., Silva, N., Andrade, C., Gomes, H. R., Império, G., Bloise, F., Kluck, G., Atella, G., et al. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.706499 · Cited by 16 · see citing works
ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons
Hasebe, R., Murakami, K., Harada, M., Halaka, N., Nakagawa, H., Kawano, F., Ohira, Y., Kawamoto, T., Yull, F. E., Blackwell, T. S., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20212019 · Cited by 21 · see citing works
Self-citationBmi1 Regulates IκBα Degradation via Association with the SCF Complex
Okuyama, Y., Tanaka, Y., Jiang, J.-J., Kamimura, D., Nakamura, A., Ota, M., Ohki, T., Higo, D., Ogura, H., Ishii, N., et al. (2018) · Journal of Immunology · doi:10.4049/jimmunol.1701223 · Cited by 16 · see citing works
“We performed quantitative PCR (qPCR) using cDNA from joint synovial cells including synovial fibroblasts (3, 34) for assessment of knockdown efficiency of Bmi1.”
BackgroundMethodResultInfluentialSelf-citationYap, J. M., Ueda, T., Kanemitsu, Y., Takeda, N., Fukumitsu, K., Fukuda, S., Uemura, T., Tajiri, T., Ohkubo, H., Maeno, K., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.921728 · Cited by 20 · see citing works
“STAT3 is known for the induction of IL6 (26).”
BackgroundCXCR1 drives the pathogenesis of EAE and ARDS via boosting dendritic cells-dependent inflammation
Zhuang, W., Zhou, J., Zhong, L., Lv, J., Zhong, X., Liu, G., Xie, L., Wang, C., Saimaier, K., Han, S., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06126-y · Cited by 19 · see citing works
The Gateway Reflex, a Novel Neuro-Immune Interaction for the Regulation of Regional Vessels
Tanaka, Y., Arima, Y., Kamimura, D., & Murakami, M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01321 · Cited by 19 · see citing works
Self-citationVenegas, F. C., Sánchez‐Rodríguez, R., Luisetto, R., Angioni, R., Viola, A., & Canton, M. (2023) · Arthritis & Rheumatology · doi:10.1002/art.42697 · Cited by 19 · see citing works
“14 Taken together, our results indicate that the inhibition of the mitochondrial enzyme MAO-B may represent a valid therapeutic strategy for the treatment of arthropathies associated with the deposition of CPP crystals, because these drugs act both through a preventive and a therapeutic protocol.”
BackgroundKyotani, Y., Itaya-Hironaka, A., Yamauchi, A., Sakuramoto-Tsuchida, S., Makino, M., Takasawa, S., & Yoshizumi, M. (2018) · FEBS Open Bio · doi:10.1002/2211-5463.12430 · Cited by 17 · see citing works
Shimoyama, S., Nakagawa, I., Jiang, J., Matsumoto, I., Chiorini, J. A., Hasegawa, Y., Ohara, O., Hasebe, R., Ota, M., Uchida, M., et al. (2021) · International Immunology · doi:10.1093/intimm/dxab025 · Cited by 17 · see citing works
Self-citationMurakami, K., Kamimura, D., Hasebe, R., Uchida, M., Abe, N., Yamamoto, R., Jiang, J., Hidaka, Y., Nakanishi, Y., Fujita, S., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.675909 · Cited by 14 · see citing works
“A type 1 collagen+ endothelial BC1 cell line was obtained from Dr. M. Miyasaka (Osaka University, Suita, Japan) (14).”
Self-citationSanjeewa, K. K. A., & Herath, K. H. I. N. M. (2023) · Fisheries and aquatic sciences · doi:10.47853/fas.2023.e6 · Cited by 13 · see citing works
“Inflammation is part of our defense mechanism (Murakami et al., 2013).”
BackgroundGateway reflex: neural activation-mediated immune cell gateways in the central nervous system
Kamimura, D., Ohki, T., Arima, Y., & Murakami, M. (2018) · International Immunology · doi:10.1093/intimm/dxy034 · Cited by 12 · see citing works
Self-citationEpiregulin is released from intervertebral disks and induces spontaneous activity in pain pathways
Kongstorp, M., Schjølberg, T., Jacobsen, D. P., Haugen, F., & Gjerstad, J. (2019) · PAIN Reports · doi:10.1097/pr9.0000000000000718 · Cited by 12 · see citing works
“In arthritis in mice, EREG induces release of cytokines and other growth factors,(7) which further may enhance the inflammation.(7,21) Recruitment of circulating macrophages and release of proinflammatory agents(17,22) promote nociceptive signaling in primary”
BackgroundKimura, A., Takagi, T., Thamamongood, T., Sakamoto, S., Ito, T., Seki, I., Okamoto, M., Aono, H., Serada, S., Naka, T., et al. (2023) · Annals of the Rheumatic Diseases · doi:10.1136/ard-2023-224055 · Cited by 11 · see citing works
Duncan, R. S., Rohowetz, L. J., Vogt, A., & Koulen, P. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.109494 · Cited by 11 · see citing works
Zhang, Z.-X., Tian, Y., Li, S., Jing, H., Cai, J., Li, M., & Xing, G. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01797-2 · Cited by 11 · see citing works
“EREG may trigger the expression of other growth factors and cytokines [76, 77], which in turn activates the PI3K/Akt pathway and the MAPK cascade that may affect nociceptive activity in the primary afferent nerve fibers [78], or in the spinal dorsal horn [79, 80].”
BackgroundKida, H., Jiang, J., Matsui, Y., Takahashi, I., Hasebe, R., Kawamura, D., Endo, T., Shibayama, H., Kondō, M., Nishio, Y., et al. (2023) · International Immunology · doi:10.1093/intimm/dxad004 · Cited by 10 · see citing works
Self-citationGateway reflexes: A new paradigm of neuroimmune interactions
Ohki, T., Kamimura, D., Arima, Y., & Murakami, M. (2017) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12378 · Cited by 10 · see citing works
Self-citationFukuda, K., Miura, Y., Maeda, T., Hayashi, S., Matsumoto, T., & Kuroda, R. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10432 · Cited by 10 · see citing works
DDX6 is involved in the pathogenesis of inflammatory diseases via NF-κB activation
Naito, S., Tanaka, H., Jiang, J., Tarumi, M., Hashimoto, A., Tanaka, Y., Murakami, K., Kubota, S. I., Hojyo, S., Hashimoto, S., et al. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.149666 · Cited by 9 · see citing works
Self-citationYou, D. J., Lee, H.-Y., Taylor-Just, A. J., & Bonner, J. (2022) · Toxicology in Vitro · doi:10.1016/j.tiv.2022.105394 · Cited by 7 · see citing works
Fatima, T., Abrar, H., Jahan, N., Shamim, S., Ahmed, N., Ali, A., Begum, I., & Ahmed, W. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1319613 · Cited by 7 · see citing works
Furukawa, R., Kuwatani, M., Jiang, J., Tanaka, Y., Hasebe, R., Murakami, K., Tanaka, K., Hirata, N., Ohki, I., Takahashi, I., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-60312-2 · Cited by 9 · see citing works
“…CLDN2, CPA1, FUT2, MORC4, SPINK1, CEL, or CFTR) have been previously identified as chronic/acute pancreatitis-related genes 3–18 , and 9 of them (GGT1, CTRB1, ABO, CTRC, CLDN2, CPA1, FUT2, CEL, CFTR) are potential regulators of the IL-6 amplifier by our results, which was reported previously 29 .”
Self-citationIL-6 and Inflammatory Diseases
Kamimura, D., Arima, Y., Hirano, T., Ogura, H., & Murakami, M. (2013) · Springer eBooks · doi:10.1007/978-4-431-54442-5_2 · Cited by 8 · see citing works
Self-citationEstablishment of Novel Murine Model showing Vascular Inflammation-derived Cognitive Dysfunction
Hashizume, T., Son, B., Taniguchi, S., Ito, K., Noda, Y., Endo, T., Nanao‐Hamai, M., Ogawa, S., & Akishita, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-40726-z · Cited by 7 · see citing works
dEREGulated pathways: unraveling the role of epiregulin in skin, kidney, and lung fibrosis
Ezaddoustdar, A., Kalina, D., Bielohuby, M., Boehm, M., & Wygrecka, M. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00813.2024 · Cited by 6 · see citing works
Computer model of IL-6-dependent rheumatoid arthritis in F759 mice
Yamamoto, R., Yamada, S., Atsumi, T., Murakami, K., Hashimoto, A., Naito, S., Tanaka, Y., Ohki, I., Shinohara, Y., Iwasaki, N., et al. (2023) · International Immunology · doi:10.1093/intimm/dxad016 · Cited by 6 · see citing works
Self-citationThe gateway reflex regulates tissue-specific autoimmune diseases
Tanaka, Y., Ohki, I., Murakami, K., Ozawa, S., Wang, Y., & Murakami, M. (2024) · Inflammation and Regeneration · doi:10.1186/s41232-024-00325-6 · Cited by 6 · see citing works
“This enhanced chemokine production is stimulated by the concurrent activation of the NF-κB and STAT3 pathways through a mechanism we call the IL-6 amplifier [20–27] (Fig.”
BackgroundSelf-citationYamasaki, T., Nagata, N., Atsumi, T., Hasebe, R., Tanaka, Y., Ohki, I., Kubota, S. I., Shinohara, Y., Teoh, Y. B., Yokoyama, N., et al. (2023) · International Immunology · doi:10.1093/intimm/dxad006 · Cited by 5 · see citing works
Self-citationGateway reflex: Local neuroimmune interactions that regulate blood vessels
Kamimura, D., Ohki, T., Arima, Y., Ota, M., & Murakami, M. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.09.011 · Cited by 5 · see citing works
Self-citationRNF213–TRAF2 interaction enhances inflammatory responses via NF-κB activation in moyamoya disease
Yasuda, M., Murakami, K., Jiang, J.-J., Ito, M., Tanaka, Y., Tanaka, H., Hasebe, R., Yamasaki, T., Hashimoto, A., Kubota, S. I., et al. (2026) · International Immunology · doi:10.1093/intimm/dxag011 · Cited by 4 · see citing works
Self-citationHayashi, Y. (2023) · Glia · doi:10.1002/glia.24476 · Cited by 4 · see citing works
“…IL-6 triggers a positive feedback loop for the NF-κ B signaling as an inflammation amplifier, leading to the development of autoimmune diseases such as F759 arthritis and experimental autoimmune encephalomyelitis, which is a model for multiple sclerosis (Arima et al., 2012; Murakami et al., 2013).”
BackgroundTu, Z., Xue, H., Chen, W., Cao, L., & Zhang, W.-Q. (2016) · Rheumatology International · doi:10.1007/s00296-016-3607-z · Cited by 4 · see citing works
Inflammation-induced cell-secreted migrasome promotes IL-6 expression in the recipient cells.
Saito, S., Yoshikawa, K., Tanaka, M., Murakami, M., & Okochi, M. (2026) · Biomaterials Advances · doi:10.1016/j.bioadv.2026.214793 · Cited by 3 · see citing works
Self-citationIdentification of PECAM1 as a Prognostic Biomarker for Lung Adenocarcinoma
Lin, S.-S., Hsu, P.-S., Lin, Y.-C., You, J., Shih, Y.-L., & Lai, H.-C. (2025) · Diagnostics · doi:10.3390/diagnostics15091094 · Cited by 2 · see citing works
Wang, Z., Qin, M., Li, Y., Li, Y., Qi, Z., Li, X., Gao, J., Luoreng, Z., & Wang, X. (2026) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.6c00186 · Cited by 2 · see citing works
Epidermal growth factor receptor signaling modulates postoperative pain and inflammatory responses
Kyomuhangi, A. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1793260 · Cited by 2 · see citing works
“Because EGFR ligands can be released into extracellular fl uids, circulating concentrations of ligands such as EREG, AREG, or HB-EGF in plasma or serum could potentially serve as non-invasive biomarkers re fl ecting in-fl ammatory pain activity (126, 130).”
Pain is an inducer for relapse in multiple sclerosis models through a regional neural signal
Arima, Y., Higuchi, K., Nishikawa, N., Štofková, A., Ohki, T., Kamimura, D., & Murakami, M. (2015) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12250 · Cited by 2 · see citing works
Self-citationKolon Kanserinde IL-6 Sitokinin Karbonik anhidraz III Gen İfadesi Üzerindeki Etkisinin İncelenmesi
BABACAN, D., Türkoğlu, S. A., & KOCKAR, F. T. (2023) · Iğdır Üniversitesi Fen Bilimleri Enstitüsü Dergisi · doi:10.21597/jist.1183875 · Cited by 2 · see citing works
Teoh, Y. B., Jiang, J., Yamasaki, T., Nagata, N., Sugawara, T., Hasebe, R., Ohta, H., Sasaki, N., Yokoyama, N., Nakamura, K., et al. (2023) · Frontiers in Veterinary Science · doi:10.3389/fvets.2023.1192888 · Cited by 2 · see citing works
Self-citationNawa, H., & Murakami, M. (2025) · Neuropsychopharmacology Reports · doi:10.1002/npr2.12520 · Cited by 2 · see citing works
Self-citationThe Reverse-Direction Method Links Mass Experimental Data to Human Diseases
Ogura, H., Atsumi, T., Bando, H., Sabharwal, L., Yamada, M., Jiang, J.-J., Nakamura, A., Arima, Y., Kamimura, D., & Murakami, M. (2013) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-013-0255-9 · Cited by 1 · see citing works
Self-citationKamimura, D., Arima, Y., Štofková, A., Nishikawa, N., Higuchi, K., Ohki, T., & Murakami, M. (2016) · InTech eBooks · doi:10.5772/62938 · Cited by 1 · see citing works
Self-citationInflammation amplifier and gateway reflex: The regulation of inflammation by neuroimmune interaction
Nakagawa, I., & Murakami, M. (2017) · Japanese Journal of Clinical Immunology · doi:10.2177/jsci.40.160 · Cited by 2 · see citing works
Self-citationEpiregulin expression and secretion is increased in castration-resistant prostate cancer
Wiesehöfer, M., Raczinski, B. B. G., Wiesehöfer, C., Dankert, J. T., Czyrnik, E. D., Spahn, M., Julio, M. K.-D., & Wennemuth, G. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1107021 · Cited by 2 · see citing works
“In BC1 or Caco-2 cells, EREG expression and secretion is increased after addition of IL-6, IL-17 or IL-1b (38, 39).”
BackgroundAkabane, K., Murakami, K., & Murakami, M. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2225215 · Cited by 1 · see citing works
Self-citationNandave, M. (2024) · Springer eBooks · doi:10.1007/978-981-97-7380-0_7 · Cited by 1 · see citing works
Neural signaling in immunology: the gateway reflex
Hasebe, R., Tanaka, H., Yamasaki, T., Murakami, K., & Murakami, M. (2025) · International Immunology · doi:10.1093/intimm/dxaf009 · Cited by 1 · see citing works
Self-citationImmune cell gateways in the central nervous system regulated by regional neural stimulations
Kamimura, D., Štofková, A., Nishikawa, N., Atsumi, T., Arima, Y., & Murakami, M. (2015) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12198 · Cited by 1 · see citing works
Self-citationGateway Reflex: A Neuro-Immune Crosstalk for Organ-Specific Disease Development
Kamimura, D., Tanaka, Y., Ohki, T., & Murakami, M. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.77112 · Cited by 1 · see citing works
Self-citationPinoresinol targets NF-κB alongside STAT3 pathway to attenuate IL-6-induced inflammationPreprint
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- Authors
- Murakami, M., Harada, M., Kamimura, D., Ogura, H., Okuyama, Y., Kumai, N., Okuyama, A., Singh, R., Jiang, J.-J., Atsumi, T., Shiraya, S., Nakatsuji, Y., Kinoshita, M., Kohsaka, H., Nishida, M., Sakoda, S., Miyasaka, N., Yamaguchi-Takihara, K., & Hirano, T.
- Affiliations
- Japan Science and Technology Agency (JP)
- The University of Osaka (JP)
- Tokyo Medical and Dental University (JP)
- National Hospital Organization (JP)
- Corresponding author
- Murakami, Masaaki
- Hirano, Toshio
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 3
- Issue
- 3
- Pages
- 946-959
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W1982931411
- Cited by
- 110
- References
- 48
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 10 · 2023: 12 · 2022: 9 · 2021: 9 · 2020: 7 · 2019: 14 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 3 · 2013: 5
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-05-30)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (22500663, 24390098, 24590583)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- NF-κB signaling, positive feedback loop, STAT3, EGF receptor, epiregulin, inflammation-related diseases, therapeutic target, autoimmune disease
- MeSH terms
- Animals, Arthritis, Rheumatoid, Cell Line, Epidermal Growth Factor, Epistasis, Genetic, Humans, Inflammation, Mice, Inbred C57BL, Multiple Sclerosis, Transcription, Genetic, Signal Transduction, Interleukin-6, Genome, Genes, erbB-1, Polymorphism, Single Nucleotide, Feedback, Physiological, Mice, Genetic Loci, Genetic Association Studies, Epiregulin
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