Fol. Biol. 2025, 71, 8-17
https://doi.org/10.14712/fb2025071010008
The Potential Inflammatory Role of IL-6 Signalling in Perturbing the Energy Metabolism Function by Stimulating the Akt-mTOR Pathway in Jurkat T Cells
References
1. 2020) Extramyocellular interleukin-6 influences skeletal muscle mitochondrial physiology through canonical JAK/STAT signaling pathways. FASEB J. 34, 14458-14472.
< , H., Ryan, Z. C., Delmotte, P. et al. (https://doi.org/10.1096/fj.202000965RR>
2. 2010) Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J. Nippon Med. Sch. 77, 97-105.
< , M., Uehara, I., Kogure, K. et al. (https://doi.org/10.1272/jnms.77.97>
3. 2021) WTD attenuating rheumatoid arthritis via suppressing angiogenesis and modulating the PI3K/AKT/mTOR/HIF-1α pathway. Front. Pharmacol. 12, 696802.
< , X., Huang, Y., Shen, P. et al. (https://doi.org/10.3389/fphar.2021.696802>
4. 2009) Neuroprotective role of lactate after cerebral ischemia. J. Cereb. Blood Flow Metab. 29, 1780-1789.
< , C., Lei, H., Thevenet, J. et al. (https://doi.org/10.1038/jcbfm.2009.97>
5. 2020) Pro- and anti-inflammatory properties of interleukin in vitro: relevance for major depression and human hippocampal neurogenesis. Int. J. Neuropsychopharmacol. 23, 738-750.
< , A., di Benedetto, M. G., Giacobbe, J. et al. (https://doi.org/10.1093/ijnp/pyaa055>
6. 2020) Association of high serum interleukin-6 levels with severe progression of rheumatoid arthritis and increased treatment response differentiating sarilumab from adalimumab or methotrexate in a post hoc analysis. Arthritis Rheumatol. 72, 1456-1466.
< , A., Schwartzman, S., Msihid, J. et al. (https://doi.org/10.1002/art.41299>
7. 2023) Lactate activates the mitochondrial electron transport chain independently of its metabolism. Mol. Cell 83, 3904-3920.e7.
< , X., Ng, C. P., Jones, O. et al. (https://doi.org/10.1016/j.molcel.2023.09.034>
8. 2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688-2697.
< , A. L., Steinberg, G. R., Macaulay, S. L. et al. (https://doi.org/10.2337/db05-1404>
9. 2019) Brain glucose metabolism: integration of energetics with function. Physiol. Rev. 99, 949-1045.
< , G. A. (https://doi.org/10.1152/physrev.00062.2017>
10. 2018) Berberine inhibits IL-21/IL-21R mediated inflammatory proliferation of fibroblast-like synoviocytes through the attenuation of PI3K/Akt signaling pathway and ameliorates IL-21 mediated osteoclastogenesis. Cytokine 106, 54-66.
< , P., Rasool, M. (https://doi.org/10.1016/j.cyto.2018.03.005>
11. 2019) A novel phytochemical, DIM, inhibits proliferation, migration, invasion and TNF-α induced inflammatory cytokine production of synovial fibroblasts from rheumatoid arthritis patients by targeting MAPK and AKT/mTOR signal pathway. Front. Immunol. 10, 1620.
< , H., Zhang, X., Zeng, Y. et al. (https://doi.org/10.3389/fimmu.2019.01620>
12. 2015) Oxidative phosphorylation versus glycolysis: what fuel do spermatozoa use? Asian J. Androl. 17, 230-235.
< , S. S., Agarwal, A., Mohanty, G. et al. (https://doi.org/10.4103/1008-682X.135123>
13. 2018) Effects of artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/AKT/mTOR signaling pathway in rat models with rheumatoid arthritis. Biomed. Pharmacother. 102, 1209-1220.
< , F. B., Qiu, H. Y. (https://doi.org/10.1016/j.biopha.2018.03.142>
14. 2017) Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways. Sci. Rep. 7, 41411.
< , W., Liu, H., Luo, T. et al. (https://doi.org/10.1038/srep41411>
15. 2007) Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes 56, 1630-1637.
< , S., Deshmukh, A., Long, Y. C. et al. (https://doi.org/10.2337/db06-1733>
16. 2005) Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol. Chem. 280, 32081-32089.
< , A., Nogueira, V., Chen, C. C. et al. (https://doi.org/10.1074/jbc.M502876200>
17. 2017) TCR signal strength regulates Akt substrate specificity to induce alternate murine Th and T regulatory cell differentiation programs. J. Immunol. 199, 589-597.
< , W. F., Boggess, W. C., Morel, P. A. (https://doi.org/10.4049/jimmunol.1700369>
18. 2003) The effect of graded exercise on IL-6 release and glucose uptake in human skeletal muscle. J. Physiol. 546, 299-305.
< , J. W., Stallknecht, B., Pedersen, B. K. et al. (https://doi.org/10.1113/jphysiol.2002.030437>
19. 2023) Blockade of interleukin-6 trans-signaling prevents mitochondrial dysfunction and cellular senescence in retinal endothelial cells. Exp. Eye Res. 237, 109721.
< , J. M., Robinson, R., Greenway, G. et al. (https://doi.org/10.1016/j.exer.2023.109721>
20. 2023) Interleukin-6 facilitates acute myeloid leukemia chemoresistance via mitofusin 1-mediated mitochondrial fusion. Mol. Cancer Res. 21, 1366-1378.
< , D., Zheng, X., Cai, D. et al. (https://doi.org/10.1158/1541-7786.MCR-23-0382>
21. 2023) Regulation of c-SMAC formation and AKT-mTOR signaling by the TSG101-IFT20 axis in CD4+ T cells. Cell. Mol. Immunol. 20, 525-539.
< , J., Kang, I., Kim, Y. et al. (https://doi.org/10.1038/s41423-023-01008-x>
22. 2005) Directing transition from innate to acquired immunity: defining a role for IL-6. J. Immunol. 175, 3463-3468.
< , S. A. (https://doi.org/10.4049/jimmunol.175.6.3463>
23. 2020) Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling. Nat. Commun. 11, 3547.
< , E., Bhattacharya, S., Massalha, H. et al. (https://doi.org/10.1038/s41467-020-17402-2>
24. 2021) Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons. J. Clin. Invest. 131, e140521.
< , T., Clasadonte, J., Imbernon, M. et al. (https://doi.org/10.1172/JCI140521>
25. 2020) Cinnamaldehyde attenuates the progression of rheumatoid arthritis through down-regulation of PI3K/AKT signaling pathway. Inflammation 43, 1729-1741.
< , X., Wang, Y. (https://doi.org/10.1007/s10753-020-01246-5>
26. 2020) Immunometabolism: from basic mechanisms to translation. Immunol. Rev. 295, 5-14.
< , L., Chaib, M., Rathmell, J. C. (https://doi.org/10.1111/imr.12858>
27. 2018) Interleukin-6 reduces β-cell oxidative stress by linking autophagy with the antioxidant response. Diabetes 67, 1576-1588.
< , M. R., Conteh, A. M., Reissaus, C. A. et al. (https://doi.org/10.2337/db17-1280>
28. 2015) IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis. Acta Neuropathol. Commun. 3, 1.
< , M., Bougoin, S., Feferman, T. (https://doi.org/10.1186/s40478-014-0179-6>
29. 2012) IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine 60, 38-42.
< , A., Raychaudhuri, S. K., Raychaudhuri, S. P. (https://doi.org/10.1016/j.cyto.2012.06.316>
30. 2017) Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice. PLoS One 12, e0178232.
< , T., Kanazawa, S., Kado, M. (https://doi.org/10.1371/journal.pone.0178232>
31. 2003) Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130. J. Immunol. 171, 3202-3209.
< , M. A., Richards, P. J., Horiuchi, S. et al. (https://doi.org/10.4049/jimmunol.171.6.3202>
32. 2017) Lactate at the crossroads of metabolism, inflammation, and autoimmunity. Eur. J. Immunol. 47, 14-21.
< , V., Bombardieri, M., Pitzalis, C. et al. (https://doi.org/10.1002/eji.201646477>
33. 2019) Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring. Cell Metab. 30, 1055-1074.e8.
< , V., Certo, M., Bulusu, V. et al. (https://doi.org/10.1016/j.cmet.2019.10.004>
34. 2023) Differential effect of lactate on synovial fibroblast and macrophage effector functions. Front. Immunol. 14, 1183825.
< , V., Nefla, M., Gauthier, V. et al. (https://doi.org/10.3389/fimmu.2023.1183825>
35. 2020) Cell energy metabolism: an update. Biochim. Biophys. Acta Bioenerg. 1861, 148276.
< , M., Bouchez, C. L., Paumard, P. et al. (https://doi.org/10.1016/j.bbabio.2020.148276>
36. 2017) Increased serum concentrations of IL-1 beta, IL-21 and Th17 cells in overweight patients with rheumatoid arthritis. Arthritis Res. Ther. 19, 111.
< , H., Nagafuchi, Y., Tsuchida, Y. (https://doi.org/10.1186/s13075-017-1308-y>
37. 2016) Lactate and its many faces. Eur. J. Paediatr. Neurol. 20, 3-10.
< , M., Leen, W. G., Wevers, R. A. et al. (https://doi.org/10.1016/j.ejpn.2015.09.008>
38. 2020) Interleukin-6: a masterplayer in the cytokine network. Oncology 98, 131-137.
< , P., Dempke, W. C. M. (https://doi.org/10.1159/000505099>
39. 2016) Measuring bioenergetics in T cells using a Seahorse Extracellular Flux Analyzer. Curr. Protoc. Immunol. 113, 3.16b.1-3.16b.14.
, G. J. W., Chang, C. H., Pearce, E. L. (
40. 2011) Akt phosphorylation on Thr308 but not on Ser473 correlates with Akt protein kinase activity in human non-small cell lung cancer. Br. J. Cancer 104, 1755-1761.
< , E. E., Elder, D. J., Thomas, E. C. (https://doi.org/10.1038/bjc.2011.132>
41. 2019) Determination of the membrane transport properties of Jurkat cells with a microfluidic device. Micromachines (Basel) 10, 832.
< , T., Peng, J., Shu, Z. et al. (https://doi.org/10.3390/mi10120832>
42. 2017) Inhibition of 6-phosphofructo-2-kinase suppresses fibroblast-like synoviocytes-mediated synovial inflammation and joint destruction in rheumatoid arthritis. Br. J. Pharmacol. 174, 893-908.
< , Y., Zeng, S., Huang, M. et al. (https://doi.org/10.1111/bph.13762>