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The Interleukin-1 Family: Back to the Future
Open accessAbstract
Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) family include six receptor chains forming four signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP), and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors, and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 family members. Moreover, IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity.
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“In addition, NLRP3 inflammasome activation reduces phagocytosis of Aβ by microglial cells, thus increasing the Aβ depositions and contributing to the pathogenesis of AD (Garlanda et al., 2013; Gold and El Khoury, 2015).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Garlanda et al., 2013
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“Interleukin-18 is a member of the large interleukin-1 family40 that has recently been associated with cytokine storm disorders.”
From Cytokine storm (2020) · cites this paper as [40]
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Cites
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The Diverse Roles of the IL-36 Family in Gastrointestinal Inflammation and Resolution
León, G., Hussey, S., & Walsh, P. T. (2020) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izaa232 · Cited by 21
Mesaros, O., Jimbu, L., Neaga, A., Popescu, C., Berceanu, I., Tomuleasa, C., Fetică, B., & Zdrenghea, M. (2020) · Biomedicines · doi:10.3390/biomedicines8110516 · Cited by 21
da Silva, F. R. P., Pessoa, L. D. S., Shin, J. I., Alves, E. H. P., Koga, R. S., Smith, C. V., Vasconcelos, D. F. P., & Pereira, A. C. T. D. C. (2020) · Cytokine · doi:10.1016/j.cyto.2020.155361 · Cited by 22
IL1RN promotes osteoblastic differentiation via interacting with ITGB3 in osteoporosis
Zou, Z., Liu, R., Wang, Y., Xing, Y., Shi, Z.-W., Wang, K., & Dong, D. (2020) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmaa174 · Cited by 22
Guo, H., Qian, L., & Cui, J. (2021) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2021.0087 · Cited by 24
Ti Ions Induce IL-1β Release by Activation of the NLRP3 Inflammasome in a Human Macrophage Cell Line
Pettersson, M., Almlin, S., Romanos, G. E., & Johansson, A. (2022) · Inflammation · doi:10.1007/s10753-022-01672-7 · Cited by 22
Emerging Effects of IL-33 on COVID-19
Gao, Y., Cai, L., Li, L., Zhang, Y., Li, J., Luo, C., Wang, Y., & Tao, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113656 · Cited by 23
Deubiquitination and stabilization of IL-33 by USP21.
Tao, L., Chen, C., Song, H., Piccioni, M., Shi, G., & Li, B. (2014) · Europe PMC (PubMed Central) · Cited by 22
Gupta, A., Montepiedra, G., Gupte, A., Zeldow, B., Jubulis, J., Detrick, B., Violari, A., Madhi, S. A., Bobat, R. A., Cotton, M. F., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148649 · Cited by 21
“The SIGIRR (also known as TIR8) region is a biologically important modulator of TLR-IL-1R signaling, inhibits NF-kappa B, modulates inflammation and in the mouse model has been shown to regulate harmful responses to infections such as TB [16].”
BackgroundZhang, Y.-J., Zhang, Q., Yang, G., Tao, J.-H., Wu, G., Huang, X., Duan, Y., Li, X.-P., Ye, D., & Wang, J. (2016) · Zeitschrift für Rheumatologie · doi:10.1007/s00393-016-0202-3 · Cited by 22
CCDC134 serves a crucial role in embryonic development
Yu, B., Zhang, T., Xia, P., Gong, X., Qiu, X., & Huang, J. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3196 · Cited by 22
“The above evidence indicates that CCDC134 may function as a cytokine that mediates immune responses and a nuclear protein, similar to high mobility group box chromosomal protein 1, interleukin-1α (IL-1α) and IL-33 (6,7).”
Shourian, M., Ralph, B., Angers, I., Sheppard, D. C., & Qureshi, S. T. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01987 · Cited by 22
Hadifar, S., Behrouzi, A., Fateh, A., Khatami, S., Jamnani, F. R., Siadat, S. D., & Vaziri, F. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27271 · Cited by 22
Nariai, Y., Kamino, H., OBAYASHI, E., Kato, H., Sakashita, G., Sugiura, T., Migita, K., Koga, T., Kawakami, A., Sakamoto, K., et al. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.01.001 · Cited by 22
Novel Immunoregulatory Functions of IL-18, an Accomplice of TGF-β1
Casu, B., Dondero, A., Regis, S., Caliendo, F., Petretto, A., Bartolucci, M., Bellora, F., Bottino, C., & Castriconi, R. (2019) · Cancers · doi:10.3390/cancers11010075 · Cited by 22
Conti, P., Gallenga, C. E., Ronconi, G., Caraffa, A., & Kritas, S. K. (2019) · Dermatologic Therapy · doi:10.1111/dth.12943 · Cited by 22
Interleukin-38 interacts with destrin/actin-depolymerizing factor in human keratinocytes
Talabot‐Ayer, D., Mermoud, L., Borowczyk, J., Drukała, J., Wolnicki, M., Modarressi, A., Boehncke, W., Brembilla, N. C., & Palmer, G. (2019) · PLoS ONE · doi:10.1371/journal.pone.0225782 · Cited by 22
“Introduction The interleukin (IL)-1 family of cytokines includes seven pro-inflammatory agonists (IL-1α IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ) and four members with antagonist or antiinflammatory activity (IL-1Ra, IL-36Ra, IL-37 and IL-38) [1].”
BackgroundWestcott, J. M., Camacho, S., Nasir, A., Huysman, M. E., Rahhal, R., Dang, T. T., Riegel, A. T., Brekken, R. A., & Pearson, G. W. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0014 · Cited by 22
“The anchoring of DNp63-induced IL1a to the plasma membrane (51) limits potential IL1a-mediated suppression to directly adjacent cells.”
BackgroundThe Functional Roles of IL-33/ST2 Axis in Ocular Diseases
Qian, Y., & Zhang, M. (2020) · Mediators of Inflammation · doi:10.1155/2020/5230716 · Cited by 22
“The IL-33/ST2L axis also has a negative feedback system as soluble ST2 and soluble IL-1RAcP complex can reversely regulate and even prevent the IL-33 activity [33].”
BackgroundAlarmin(g) the innate immune system to invasive fungal infections
Caffrey, A. K., & Obar, J. J. (2016) · Current Opinion in Microbiology · doi:10.1016/j.mib.2016.06.002 · Cited by 22
“The early wave is IL-1RI/MyD88-dependent, while the late wave is CARD9-dependent.”
InfluentialAtherosclerosis as an inflammatory disease: Doubts? No more
Vaccarezza, M., Balla, C., & Rizzo, P. (2018) · IJC Heart & Vasculature · doi:10.1016/j.ijcha.2018.03.003 · Cited by 22
Atrial cardiomyocyte-restricted cleavage of gasdermin D promotes atrial arrhythmogenesis
Yuan, Y., Martsch, P., Chen, X., Martinez, E., Li, L., Song, J., Poppenborg, T., Bruns, F., Kim, J. H., Kamler, M., et al. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf024 · Cited by 23
“18 Although prior studies suggest that GSDMD activation could contribute to myocardial infarction and pathological cardiac hypertrophy by causing pyroptosis, the precise function of GSDMD in the heart, particularly in cardiomyocytes, remains poorly understood.”
Zeng, S., Bick, J., Kradolfer, D., Knubben, J., Flöter, V. L., Bauersachs, S., & Ulbrich, S. E. (2019) · BMC Genomics · doi:10.1186/s12864-019-6044-z · Cited by 21
Interleukin-1β Protection Against Experimental Sepsis in Mice
Guo, H., Shi, F., Zhou, Q., Liu, Q.-Y., Wang, Y.-X., Yang, S. T., Wu, Z., Shi, Y., Zhang, L., Xu, K.-Z., et al. (2020) · Inflammation · doi:10.1007/s10753-020-01341-7 · Cited by 21
Maruzuru, Y., Koyanagi, N., Kato, A., & Kawaguchi, Y. (2020) · Journal of Virology · doi:10.1128/jvi.02172-20 · Cited by 21
“pCA7-NLRP3, pCA7-ASC, pCA7-pro-IL-1b, pCA7-pro-caspase-1, CA7-Flag-NLRP3, pCA7AIM2, pFlag-CMV2-HSV-1/VP22, pFlag-CMV2-HSV-1/VP22(40-301), pFlag-CMV2-HSV-1/VP22(80-301), pFlag-CMV2-HSV-1/VP22(120-301), pFlag-CMV2-HSV-1/VP22(1-267), pFlag-CMV2-HSV-1/VP22(1-226), pFlag-CMV2-HSV-1/VP22(1-192), and pFlag-CMV2-HSV-1/VP22(1-…”
Posttranslational modifications as therapeutic targets for intestinal disorders
Choo, J., Heo, G., Pothoulakis, C., & Im, E. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2020.105412 · Cited by 21
Simanullang, R. H., Situmorang, P. C., Herlina, M., Noradina, N., Silalahi, B., & Manurung, S. S. (2022) · Saudi Journal of Biological Sciences · doi:10.1016/j.sjbs.2021.12.065 · Cited by 21
“a critical role in the innate immune system (Garlanda et al., 2013).”
BackgroundZhang, P., Gu, Y., Fang, H., Cao, Y., Wang, J., Liu, H., Zhang, H., He, L., He, H., Li, R., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004047 · Cited by 25
Pathophysiological Effects of Various Interleukins on Primary Cell Types in Common Heart Disease
Liu, Y., Zhang, D., & Yin, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076497 · Cited by 21
“To date, the IL-1 family has expanded to include 11 members (IL-1α, IL-1β, IL-1ra, IL-18, IL-33, IL-36Ra, IL-36α, IL-36β, IL-36γ, IL-37, and IL-38), with most of them being proinflammatory, while IL-1ra, IL-36Ra, IL-37, and IL-38 are anti-inflammatory [6].”
BackgroundInterleukin-1 receptor antagonist: a promising cytokine against human squamous cell carcinomas
Ding, Y., Yi, J., Wang, J., & Sun, Z. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e14960 · Cited by 21
“IL-1 superfamily include two interleukin-1 isoforms (IL1A and IL1B), three receptor antagonists (IL1RA, IL36RA and IL-38), IL-33, IL-18, IL-36 (A and G) and IL-37, all acting individually or cooperatively in auto-inflammatory, autoimmune, infectious and degenerative diseases [17,18].”
InfluentialNaef, P., Radpour, R., Jaeger-Ruckstuhl, C. A., Bodmer, N., Baerlocher, G. M., Döhner, H., Döhner, K., Riether, C., & Ochsenbein, A. F. (2023) · Science Signaling · doi:10.1126/scisignal.add7705 · Cited by 21
Tsuji, G., Yamamura, K., Kawamura, K., Kido-Nakahara, M., Ito, T., & Nakahara, T. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914633 · Cited by 21
“Interleukin (IL)-33 and IL-37 have been identified as novel cytokines involved in various inflammatory diseases [1,2].”
IL-1R1 is expressed on both Helios+ and Helios−FoxP3+CD4+ T cells in the rheumatic joint
Müller, M., Herrath, J., & Malmström, V. (2015) · Clinical & Experimental Immunology · doi:10.1111/cei.12668 · Cited by 21
Hoyt, T., Dobrinen, E., Kochetkova, I., & Meissner, N. N. (2014) · Infection and Immunity · doi:10.1128/iai.02639-14 · Cited by 21
TCRVγ9 γδ T Cell Response to IL-33: A CD4 T Cell–Dependent Mechanism
Duault, C., Franchini, D., Familliades, J., Cayrol, C., Roga, S., Girard, J., Fournié, J., & Poupot, M. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500260 · Cited by 22
“Discussion IL-33 has emerged as a pleiotropic immune regulator, implicated in the Th2, T regulatory, and Th1-type immune responses (41).”
Background
Metadata
- Authors
- Garlanda, C., Dinarello, C. A., & Mantovani, A.
- Affiliations
- Radboud University Medical Center (NL)
- University of Milan (IT)
- Corresponding author
- Mantovani, Alberto
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 39
- Issue
- 6
- Pages
- 1003-1018
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3933951
- OpenAlex
- W2145866317
- Cited by
- 1,945
- References
- 151
- Citations by year
- 2026: 80 · 2025: 118 · 2024: 136 · 2023: 122 · 2022: 168 · 2021: 172 · 2020: 202 · 2019: 165 · 2018: 194 · 2017: 192 · 2016: 171 · 2015: 156 · 2014: 66 · 2013: 1
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- European Research Council
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health (A115614, AR-45584)
- European Commission (FP7-HEALTH-2011- ADITEC 280873)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- interleukin-1 family, innate immunity, inflammation, IL-1 receptor family, interleukin-1 receptor antagonist, decoy receptor, IL-18, IL-33, IL-36, IL-37, IL-38, IL1RAP, SIGIRR, negative regulation of cytokine signaling, lymphocyte differentiation, innate and adaptive immunity
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Immunity, Innate, Interleukin-1, Interleukins, Ligands, Receptors, Interleukin-1, Adaptive Immunity
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