Interleukin-11 (IL-11)

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Interleukin-11 (IL-11) is a pleiotropic cytokine that belongs to glycoprotein 130 (gp130) family.[1] Due to this, it has much in common with the proteins of the IL-6 family of cytokines.[2] However, IL-6 family cytokines signal predominantly via JAK/STAT, whereas IL-11 has been shown to activate ERK in fibroblasts without a detectable transcriptional (STAT-mediated) response.[3]

IL-11 in Hematopoiesis

Interleukin-11 plays a significant role in the synthesis and maturation of hematopoietic cells, inhibition of adipogenesis, regulation of embryo implantation, and trophoblasts invasion. IL-11 is a potent hematopoietic stimulator following radiation therapy and chemotherapy, and markedly increases platelet counts. Recombinant IL-11 (Oprelvekin, trade name Neumega) is approved by the FDA to treat thrombocytopenia following radiation treatment in humans.[4]

Inhibition of IL-11 may be a potent contraceptive

[5]

IL-11 in the lung

IL-11 plays a role in viral airway disorders; human stromal cells stimulated with respiratory syncytial virus, rhinovirus, and parainfluenza virus type 3 secrete high levels of IL-11. However, IL-11 activity does not alter the initial immune responses and bacterial clearance in the context of acute respiratory infections.[6] Interleukin-11 (IL-11) is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL-11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung.[7] IL-11 and and its cognate receptor IL-11Rα are overexpressed in pulmonary arteries of pulmonary hypertension associated to IPF patients, and contributes to pulmonary artery remodeling and pulmonary hypertension.[8][9] Interleukin-11 negatively impacts lung epithelial regeneration by inhibiting progenitor cell activation and suppressing alveolar differentiation.[10] Arachidonic acid (AA) increased mRNA expression and secretion of IL-11 in lung fibroblasts in a dose-dependent manner that was dependent on the activation of the p38 or ERK MAPK signaling pathways.[11]

IL‐11 is highly expressed in the prematurely aged lung tissues of mice,[12] while the expression of Sirt1 diminishes with physiological aging in mice. Sirt1 overexpression reduced signs of aging, in particular decreased pulmonary SA-β-gal and p16- and p53-positive cells, as well as expression of p16, p19, p21, and p53; improved pulmonary dysfunction, DNA damage, senescence‐associated secretory phenotype, and fibrosis through downregulating TGF‐β1/IL‐11/MEK/ERK signaling.[13]

IL-11 is a crucial determinant of cardiovascular fibrosis

In the heart, IL-11 has been identified as a key fibrotic factor, acting downstream of the main fibrotic factor TGFβ1, driving fibrotic protein synthesis.[14] [15] IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes that establish IL11 as a disease factor. As compared to wild-type controls, Il11 expressing mouse hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors and increased inflammatory cells.[16]

Interleukin-11 in Pathologies of the Nervous System

[17] [18] [19]

IL-11 can increase the tumorigenic capacity of cells

IL11 can cause senescence

Female Il11-deleted mice are protected from age-associated obesity, frailty, and metabolic decline.[20]

As mice age, IL11 is progressively upregulated in liver, skeletal muscle, and fat to stimulate an ERK/AMPK/mTORC1 axis of cellular, tissue- and organismal-level ageing pathologies. In old mice, deletion of Il11 or Il11ra1 protects against metabolic multi-morbidity, sarcopenia, and frailty. Administration of anti-IL11 therapy to elderly mice for six months reactivates an age-repressed program of white fat beiging, reverses metabolic dysfunction, restores muscle function, and reduces frailty. Across studies, inhibition of IL11 lowers epigenetic age, reduces telomere attrition, and preserves mitochondrial function.[20] Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%.[21]

Small moleculas and inhibitors

Blockage of sgp130Fc (by TJ301 (sgp130Fc)) or inhibition of the JAK2/STAT3 pathway (by WP1066 (a JAK2/STAT3 inhibitor)) could ameliorate the profibrotic effect of IL-11.[22]

Current IL-11 signalling inhibitors include antibodies against either IL-11 or IL-11Rα and IL-11 mutants, especially a cytokine variant, IL-11 Mutein, which potently inhibits IL-11 signaling in human cells.[23]

One important next step would be to test candidate IL-11 drugs in mice with diverse genetic backgrounds and in multiple laboratories to be sure that the results are reproducible. Beyond that, determining the effect of anti-IL-11 drug candidates on longevity in people could be a challenge. Instead researchers might do well to focus on a specific condition associated with ageing.[24]

Understanding interleukin 11 as a disease gene and therapeutic target

[25]

Also see video from The Aging and Drug Discovery Conference (ARDD) 2022. Stuart Cook's report: The IL-11/ERK/mTOR axis is a target for extending mammalian healthspan and from AnaBios Antibody Mediated Blockade of Interleukin-11 Signaling for IPF & Other Fibrotic Diseases

References

  1. ↑ Cook, S. A., & Schafer, S. (2020). Hiding in plain sight: interleukin-11 emerges as a master regulator of fibrosis, tissue integrity, and stromal inflammation. Annual Review of Medicine, 71, 263-276. PMID: 31986085 DOI: 10.1146/annurev-med-041818-011649
  2. ↑ Metcalfe, R. D., Putoczki, T. L., & Griffin, M. D. (2020). Structural understanding of interleukin 6 family cytokine signaling and targeted therapies: focus on interleukin 11. Frontiers in Immunology, 11, 1424. PMID: 32765502 PMC7378365 DOI: 10.3389/fimmu.2020.01424
  3. ↑ Garbers, C., & Scheller, J. (2013). Interleukin-6 and interleukin-11: same same but different. Biological chemistry, 394(9), 1145-1161. PMID: 23740659 DOI: 10.1515/hsz-2013-0166
  4. ↑ Wilde, M. I., & Faulds, D. (1998). Oprelvekin: a review of its pharmacology and therapeutic potential in chemotherapy-induced thrombocytopenia. BioDrugs, 10(2), 159-171. PMID: 18020592 DOI: 10.2165/00063030-199810020-00006
  5. ↑ Menkhorst, E., Salamonsen, L., Robb, L., & Dimitriadis, E. (2009). IL11 antagonist inhibits uterine stromal differentiation, causing pregnancy failure in mice. Biology of reproduction, 80(5), 920-927. PMID: 19144959 PMC2849829 DOI: 10.1095/biolreprod.108.073601
  6. ↑ Einarsson, O., Geba, G. P., Zhu, Z., Landry, M., & Elias, J. A. (1996). Interleukin-11: stimulation in vivo and in vitro by respiratory viruses and induction of airways hyperresponsiveness. The Journal of clinical investigation, 97(4), 915-924. PMID: 8613544 PMC507136 DOI: 10.1172/JCI118514
  7. ↑ Ng, B., Dong, J., D’Agostino, G., Viswanathan, S., Widjaja, A. A., Lim, W. W., ... & Cook, S. A. (2019). Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Science Translational Medicine, 11(511), eaaw1237.PMID: 37228276 PMC10204861 DOI: 10.1183/23120541.00679-2022
  8. ↑ Milara, J., Roger, I., Montero, P., Artigues, E., Escrivá, J., & Cortijo, J. (2022). IL-11 system participates in pulmonary artery remodeling and hypertension in pulmonary fibrosis. Respiratory Research, 23(1), 1-18. PMID: 36376885 PMC9664718 DOI: 10.1186/s12931-022-02241-0
  9. ↑ Ng, B., Dong, J., D’Agostino, G., Viswanathan, S., Widjaja, A. A., Lim, W. W., ... & Cook, S. A. (2019). Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Science Translational Medicine, 11(511), eaaw1237. PMID: 31554736 DOI: 10.1126/scitranslmed.aaw1237
  10. ↑ Kortekaas, R. K., Geillinger-Kästle, K. E., Borghuis, T., Belharch, K., Webster, M., Timens, W., ... & Gosens, R. (2023). Interleukin-11 disrupts alveolar epithelial progenitor function. ERJ Open Research, 9(3). PMID: 37228276 PMC10204861 DOI: 10.1183/23120541.00679-2022
  11. ↑ Sasaki, K., Komamura, S., & Matsuda, K. (2023). Extracellular stimulation of lung fibroblasts with arachidonic acid increases interleukin 11 expression through p38 and ERK signaling. Biological Chemistry, 404(1), 59-69. PMID: 36268909 DOI: 10.1515/hsz-2022-0218
  12. ↑ Chen, H., Chen, H., Liang, J., Gu, X., Zhou, J., Xie, C., ... & Jin, J. (2020). TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency. Experimental & Molecular Medicine, 52(1), 130-151. PMID: 31959867 PMC7000795 DOI: 10.1038/s12276-019-0371-7
  13. ↑ Zhou, J., Chen, H., Wang, Q., Chen, S., Wang, R., Wang, Z., ... & Jin, J. (2022). Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription. Aging Cell, 21(8), e13680.
  14. ↑ Schafer, S., Viswanathan, S., Widjaja, A. A., Lim, W. W., Moreno-Moral, A., DeLaughter, D. M., ... & Cook, S. A. (2017). IL-11 is a crucial determinant of cardiovascular fibrosis. Nature, 552(7683), 110-115. PMID: 29160304 PMC5807082 DOI: 10.1038/nature24676
  15. ↑ Wu, J., Ma, W., Qiu, Z., & Zhou, Z. (2023). Roles and mechanism of IL-11 in vascular diseases. Frontiers in cardiovascular medicine, 10, 1171697. PMID: 37304948 PMC10250654 DOI: 10.3389/fcvm.2023.1171697
  16. ↑ Sweeney, M. D., O'Fee, K., Villanueva-Hayes, C., Rahman, E., Lee, M., Andrew, I., ... & Cook, S. A. (2023). Cardiomyocyte-restricted expression of IL11 causes cardiac fibrosis, inflammation, and dysfunction. bioRxiv, 2023-05. https://doi.org/10.1101/2023.05.23.541928
  17. ↑ Seyedsadr, M., Wang, Y., Elzoheiry, M., Shree Gopal, S., Jang, S., Duran, G., ... & Markovic-Plese, S. (2023). IL-11 induces NLRP3 inflammasome activation in monocytes and inflammatory cell migration to the central nervous system. Proceedings of the National Academy of Sciences, 120(26), e2221007120. PMID: 37339207 PMC10293805 (available on 2023-12-20) DOI: 10.1073/pnas.2221007120
  18. ↑ Airapetov, M. I., Eresko, S. O., Ignatova, P. D., Lebedev, A. A., Bychkov, E. R., & Shabanov, P. D. (2023). Interleukin-11 in Pathologies of the Nervous System. Molecular Biology, 57(1), 1-6. PMID: 37016665 PMCID: PMC10062686 DOI: 10.1134/S0026893323010028
  19. ↑ Airapetov, M., Eresko, S., Ignatova, P., Lebedev, A., Bychkov, E., & Shabanov, P. (2022). A brief summary regarding the roles of interleukin-11 in neurological diseases. BioScience Trends, 16(5), 367-370. PMID: 36261332 DOI: 10.5582/bst.2022.01331
  20. ↑ 20.0 20.1 Widjaja, A. A., Lim, W. W., Viswanathan, S., Chothani, S., Corden, B., Goh, J. W. T., ... & Cook, S. A. (2023). Inhibition of an immunometabolic axis of mTORC1 activation extends mammalian healthspan. bioRxiv, 2023-07. https://doi.org/10.1101/2023.07.09.548250
  21. ↑ Widjaja, A.A., Lim, WW., Viswanathan, S. et al. (2024). Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature. 632, 157–165 https://doi.org/10.1038/s41586-024-07701-9
  22. ↑ Ye, W., Wang, Q., Zhao, L., Wang, C., Zhang, D., Zhou, M., ... & Xue, Y. (2023). Blockade of IL-11 Trans-Signaling or JAK2/STAT3 Signaling Ameliorates the Profibrotic Effect of IL-11. Immunological Investigations, 52(6), 703-716. PMID: 37401665 DOI: 10.1080/08820139.2023.2222746
  23. ↑ Metcalfe, R. D., Hanssen, E., Fung, K. Y., Aizel, K., Kosasih, C. C., Zlatic, C. O., ... & Griffin, M. D. (2023). Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant. Nature Communications, 14(1), 7543. PMID: 37985757 PMC10662374 DOI: 10.1038/s41467-023-42754-w
  24. ↑ Ledford H. (2024). Mice live longer when inflammation-boosting protein is blocked. Humans also have the protein, called IL-11, offering hope for a future longevity treatment. Nature (News)
  25. ↑ Cook, S. A. (2023). Understanding interleukin 11 as a disease gene and therapeutic target. Biochemical journal, 480(23), 1987-2008. PMID: 38054591 PMC10754292 DOI: 10.1042/BCJ20220160
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