The impact of interleukin-6 (IL-6) and mesenchymal stem cell-derived IL-6 on neurological conditions.

Irina Kerkis, ��lvaro Prieto da Silva, Rodrigo Pinheiro Araldi
Author Information
  1. Irina Kerkis: Genetics Laboratory, Center of Development and Innovation, Butantan Institute, S��o Paulo, Brazil.
  2. ��lvaro Prieto da Silva: Genetics Laboratory, Center of Development and Innovation, Butantan Institute, S��o Paulo, Brazil.
  3. Rodrigo Pinheiro Araldi: BioDecision Analytics Ltda., S��o Paulo, Brazil.

Abstract

Interleukin-6 (IL-6) is a versatile cytokine crucial for immune response modulation, inflammation regulation, and various physiological processes in the body. Its wide-ranging functions underscore its importance in maintaining health. Dysregulated IL-6 is closely associated with many diseases, making it a key research and therapeutic target. Elevated IL-6 levels in the central nervous system worsen neuroinflammation in neurodegenerative diseases by activating microglia and astrocytes and releasing pro-inflammatory cytokines and neurotoxic molecules. Moreover, dysregulated IL-6 weakens the blood-brain barrier, exacerbating neuroinflammation and neuronal damage by allowing peripheral immune cells and inflammatory mediators to enter the brain. Mesenchymal stem cells (MSCs) show promise in modulating neuroinflammation by regulating IL-6 levels. They effectively suppress pro-inflammatory cytokines, including IL-6, while promoting anti-inflammatory factors. This therapeutic approach highlights the importance of targeting IL-6 and other inflammatory mediators to alleviate neuroinflammation and its adverse effects on neurological disorders. This review provides a comprehensive overview of IL-6's involvement in neurological disorders, examining endogenous IL-6 and IL-6 derived from MSCs. We explore IL-6's mechanisms affecting neuronal function, survival, and immune modulation in the central nervous system. Additionally, we discuss the potential of MSC-derived IL-6 in neuroregeneration and neuroprotection. By elucidating IL-6's interplay with neurological pathologies, this review offers insights into novel therapeutic strategies targeting IL-6 signaling pathways for neurological disorders.

Keywords

References

  1. Expert Rev Clin Pharmacol. 2022 May;15(5):575-592 [PMID: 35791866]
  2. Cell Rep. 2022 Feb 15;38(7):110358 [PMID: 35172141]
  3. Brain Behav Immun. 2016 Nov;58:181-190 [PMID: 27395434]
  4. Nat Cell Biol. 2010 Feb;12(2):153-63 [PMID: 20081841]
  5. Lupus. 2004;13(5):339-43 [PMID: 15230289]
  6. PLoS Pathog. 2023 Apr 26;19(4):e1011320 [PMID: 37099596]
  7. Cell Mol Life Sci. 2017 Jul;74(13):2345-2360 [PMID: 28214990]
  8. J Neurol Sci. 2019 Mar 15;398:50-53 [PMID: 30682521]
  9. Sci Rep. 2020 Dec 14;10(1):21853 [PMID: 33318571]
  10. Front Neuroendocrinol. 2020 Oct;59:100857 [PMID: 32781194]
  11. Cells. 2020 Aug 07;9(8): [PMID: 32784608]
  12. Neurosci Lett. 2008 Aug 22;441(2):158-62 [PMID: 18582534]
  13. Semin Cell Dev Biol. 2017 Jul;67:56-64 [PMID: 27871993]
  14. Neurochem Res. 2024 Apr;49(4):834-846 [PMID: 38227113]
  15. Immunity. 2017 Feb 21;46(2):220-232 [PMID: 28228280]
  16. Int J Mol Sci. 2022 Nov 23;23(23): [PMID: 36498901]
  17. J Physiol. 2000 Aug 1;526 Pt 3:653-61 [PMID: 10922015]
  18. Curr Osteoporos Rep. 2015 Jun;13(3):131-9 [PMID: 25712618]
  19. Neuronal Signal. 2023 Dec 04;7(4):NS20220063 [PMID: 38059210]
  20. Eur J Med Res. 2023 Jan 27;28(1):47 [PMID: 36707899]
  21. Mediators Inflamm. 2017;2017:3908061 [PMID: 28316374]
  22. PLoS One. 2017 May 23;12(5):e0178232 [PMID: 28542434]
  23. Neurosci Lett. 2010 Jan 1;468(1):56-8 [PMID: 19857551]
  24. J Neuroimmunol. 2004 Oct;155(1-2):43-54 [PMID: 15342195]
  25. Int J Mol Sci. 2023 Aug 21;24(16): [PMID: 37629202]
  26. Int Immunopharmacol. 2022 Oct;111:109130 [PMID: 35969896]
  27. Stem Cell Res Ther. 2017 Apr 17;8(1):79 [PMID: 28412968]
  28. Front Mol Neurosci. 2019 Oct 25;12:258 [PMID: 31708741]
  29. Parkinsons Dis. 2015;2015:898192 [PMID: 26351617]
  30. Brain Behav Immun Health. 2023 May 05;30:100635 [PMID: 37215308]
  31. Cytokine. 2021 Aug;144:155582 [PMID: 34058569]
  32. Front Immunol. 2023 Sep 28;14:1255533 [PMID: 37841263]
  33. Trends Pharmacol Sci. 2020 Sep;41(9):653-664 [PMID: 32709406]
  34. Alzheimers Dement (N Y). 2018 Sep 06;4:575-590 [PMID: 30406177]
  35. Neurol Neuroimmunol Neuroinflamm. 2021 Oct 19;8(6): [PMID: 34667128]
  36. Muscle Nerve. 1998 Jun;21(6):819-22 [PMID: 9585342]
  37. J Tissue Eng Regen Med. 2022 Mar;16(3):244-253 [PMID: 34890489]
  38. Cells. 2023 Sep 15;12(18): [PMID: 37759507]
  39. Am J Physiol Regul Integr Comp Physiol. 2010 Jul;299(1):R343-51 [PMID: 20427720]
  40. Front Mol Neurosci. 2022 Oct 24;15:1013933 [PMID: 36353359]
  41. J Mol Biol. 1997 May 2;268(2):468-81 [PMID: 9159484]
  42. Front Cell Dev Biol. 2023 Sep 07;11:1244120 [PMID: 37745306]
  43. Nat Commun. 2021 Jan 15;12(1):391 [PMID: 33452250]
  44. J Inflamm Res. 2023 May 16;16:2089-2119 [PMID: 37215379]
  45. Arthritis Res Ther. 2006;8 Suppl 2:S3 [PMID: 16899107]
  46. Cold Spring Harb Perspect Biol. 2014 Sep 04;6(10):a016295 [PMID: 25190079]
  47. Brain Behav Immun Health. 2022 Mar 07;21:100442 [PMID: 35308082]
  48. Front Aging Neurosci. 2020 Nov 04;12:580068 [PMID: 33328961]
  49. Mol Neurodegener. 2020 May 24;15(1):29 [PMID: 32448329]
  50. Cells. 2022 Nov 21;11(22): [PMID: 36429126]
  51. Ann Neurol. 2005 Feb;57(2):176-9 [PMID: 15668963]
  52. Int J Mol Sci. 2021 Sep 30;22(19): [PMID: 34638927]
  53. Cell Death Dis. 2016 Jan 21;7:e2062 [PMID: 26794657]
  54. Pharmaceutics. 2022 Feb 09;14(2): [PMID: 35214113]
  55. J Neurosci. 1995 Oct;15(10):6688-99 [PMID: 7472429]
  56. Genes Dev. 1991 May;5(5):728-40 [PMID: 1709130]
  57. Oncotarget. 2018 Apr 3;9(25):17443-17454 [PMID: 29707119]
  58. J Neurotrauma. 2023 Nov;40(21-22):2249-2269 [PMID: 37166354]
  59. Nat Rev Immunol. 2023 Oct;23(10):666-681 [PMID: 37069261]
  60. Stem Cell Res Ther. 2018 Jan 22;9(1):13 [PMID: 29357923]
  61. Biomedicines. 2020 Apr 30;8(5): [PMID: 32365896]
  62. J Cell Commun Signal. 2023 Mar;17(1):55-74 [PMID: 36112307]
  63. Front Immunol. 2023 Jun 05;14:1160148 [PMID: 37342352]
  64. Rheumatology (Oxford). 2023 Dec 1;62(12):3804-3810 [PMID: 37594751]
  65. Clin Pharmacol Ther. 2017 Oct;102(4):591-598 [PMID: 28675418]
  66. Stem Cell Res Ther. 2016 Sep 09;7(1):131 [PMID: 27612948]
  67. Stem Cells Int. 2019 Jul 29;2019:9281329 [PMID: 31467565]
  68. Cell Commun Signal. 2019 May 17;17(1):46 [PMID: 31101051]
  69. iScience. 2021 Sep 16;24(10):103141 [PMID: 34646984]
  70. Cell Mol Immunol. 2023 Jun;20(6):558-569 [PMID: 36973490]
  71. Front Neurosci. 2021 Feb 26;15:641157 [PMID: 33716657]
  72. J Inflamm Res. 2022 Jan 26;15:573-593 [PMID: 35115806]
  73. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3251-6 [PMID: 9501249]
  74. Front Immunol. 2022 Dec 22;13:1088124 [PMID: 36618375]
  75. Commun Biol. 2019 Jan 18;2:27 [PMID: 30675525]
  76. Genes (Basel). 2022 May 26;13(6): [PMID: 35741711]
  77. Int J Cell Cloning. 1990 Jan;8 Suppl 1:155-66; discussion 166-7 [PMID: 2324554]
  78. Front Physiol. 2023 Jul 24;14:1110926 [PMID: 37555019]
  79. J Exp Med. 1996 Apr 1;183(4):1399-406 [PMID: 8666898]
  80. Transl Psychiatry. 2021 Apr 28;11(1):251 [PMID: 33911072]
  81. Brain Behav Immun. 2017 May;62:11-23 [PMID: 27838335]
  82. Brain Res Rev. 2011 Jun 24;67(1-2):157-83 [PMID: 21238488]
  83. J Exp Med. 2021 Jul 5;218(7): [PMID: 34129018]
  84. BMC Dev Biol. 2019 Feb 1;19(1):2 [PMID: 30709330]
  85. Int J Mol Sci. 2013 Jul 04;14(7):13931-57 [PMID: 23880850]
  86. Neurol Neuroimmunol Neuroinflamm. 2023 Feb 21;10(3): [PMID: 36810164]
  87. Stem Cell Res Ther. 2018 Oct 25;9(1):286 [PMID: 30359316]
  88. Front Cell Neurosci. 2020 Jun 23;14:120 [PMID: 32655367]
  89. JCI Insight. 2024 Feb 8;9(3): [PMID: 38329129]
  90. Arthritis Res Ther. 2020 Oct 20;22(1):250 [PMID: 33081825]
  91. Neural Regen Res. 2016 Dec;11(12):1922-1923 [PMID: 28197184]
  92. Cell Biosci. 2021 Feb 23;11(1):41 [PMID: 33622388]
  93. Neuropsychiatr Dis Treat. 2023 Oct 30;19:2319-2329 [PMID: 37928166]
  94. Stem Cell Res. 2018 Jul;30:100-112 [PMID: 29843002]
  95. Front Immunol. 2021 Feb 05;11:591065 [PMID: 33613514]
  96. Brain. 2014 Mar;137(Pt 3):819-33 [PMID: 24459107]
  97. J Exp Med. 2020 Jan 6;217(1): [PMID: 31611251]
  98. Exp Mol Med. 2019 Oct 24;51(10):1-12 [PMID: 31649245]
  99. J Cell Biochem. 2009 Oct 15;108(3):577-88 [PMID: 19650110]
  100. Trends Endocrinol Metab. 2023 Nov;34(11):749-763 [PMID: 37633799]
  101. Curr Pharm Des. 2010;16(6):684-91 [PMID: 20388078]
  102. Cytokine. 2021 Dec;148:155684 [PMID: 34411990]
  103. Eur J Neurosci. 2001 Dec;14(11):1753-61 [PMID: 11860469]
  104. Mol Biol Cell. 2009 Jan;20(1):188-99 [PMID: 18971377]
  105. Brain Behav Immun Health. 2022 Sep 24;26:100522 [PMID: 36187407]
  106. Br J Anaesth. 2022 Dec;129(6):923-936 [PMID: 36253222]
  107. J Immunol. 2012 Aug 15;189(4):1928-36 [PMID: 22798669]
  108. Inflammopharmacology. 2019 Aug;27(4):663-677 [PMID: 30874945]
  109. Nat Rev Rheumatol. 2020 Jun;16(6):335-345 [PMID: 32327746]
  110. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15959-64 [PMID: 12461182]
  111. Semin Immunol. 2014 Feb;26(1):1 [PMID: 24556601]
  112. FEBS Lett. 1989 Jan 2;242(2):237-9 [PMID: 2464504]
  113. Front Pharmacol. 2021 Jan 25;11:590470 [PMID: 33716723]
  114. Biochem Biophys Res Commun. 2006 Apr 21;342(4):1396-404 [PMID: 16516857]
  115. Stem Cells Transl Med. 2020 Oct;9(10):1174-1189 [PMID: 32573961]
  116. Cytokine. 2022 Jan;149:155742 [PMID: 34688020]
  117. Cell Stem Cell. 2022 Nov 3;29(11):1515-1530 [PMID: 36332569]
  118. Front Immunol. 2018 Mar 23;9:585 [PMID: 29662491]
  119. Trends Immunol. 2015 Feb;36(2):92-101 [PMID: 25616716]
  120. Stem Cells. 2020 May;38(5):596-605 [PMID: 31995249]
  121. Neurobiol Dis. 2020 Sep;143:104963 [PMID: 32593752]
  122. BMC Dev Biol. 2021 Jan 12;21(1):3 [PMID: 33430761]
  123. Int J Biol Sci. 2012;8(9):1254-66 [PMID: 23136554]
  124. Endocrinology. 2009 Apr;150(4):1850-60 [PMID: 19022895]
  125. Eye (Lond). 2017 Feb;31(2):173-178 [PMID: 27886185]
  126. Sci Rep. 2016 Jan 14;6:18587 [PMID: 26766745]
  127. Front Microbiol. 2019 May 10;10:1057 [PMID: 31134045]
  128. Exp Neurol. 2004 Dec;190(2):446-55 [PMID: 15530883]
  129. Front Immunol. 2020 Jul 16;11:1424 [PMID: 32765502]
  130. Amyotroph Lateral Scler Frontotemporal Degener. 2021 May;22(3-4):248-259 [PMID: 32924606]
  131. J Exp Med. 2023 Nov 6;220(11): [PMID: 37584653]
  132. Int J Mol Sci. 2021 Oct 13;22(20): [PMID: 34681685]
  133. Acta Neurol Scand. 1998 Aug;98(2):142-4 [PMID: 9724016]
  134. Int J Mol Sci. 2022 May 29;23(11): [PMID: 35682773]
  135. Front Physiol. 2020 Dec 22;11:593026 [PMID: 33414722]
  136. J Cereb Blood Flow Metab. 2015 May;35(5):747-50 [PMID: 25757748]
  137. Curr Neuropharmacol. 2022;20(6):1116-1143 [PMID: 34852742]
  138. J Biol Chem. 2013 Jan 18;288(3):1489-99 [PMID: 23184935]
  139. Tumour Biol. 2016 Sep;37(9):11553-11572 [PMID: 27260630]
  140. Ther Adv Musculoskelet Dis. 2010 Oct;2(5):247-56 [PMID: 22870451]
  141. Neuropharmacology. 2015 Sep;96(Pt A):42-54 [PMID: 25445486]
  142. Eur J Med Res. 2023 Feb 20;28(1):86 [PMID: 36803566]
  143. Cytotherapy. 2014 Oct;16(10):1336-44 [PMID: 24927715]
  144. Int Immunopharmacol. 2021 Jan;90:106788 [PMID: 32718866]
  145. J Neuroimmunol. 1996 Jan;64(1):37-43 [PMID: 8598388]
  146. Cell Death Discov. 2020 Jun 2;6:42 [PMID: 32528731]
  147. Biochim Biophys Acta. 2016 Jun;1863(6 Pt A):1218-27 [PMID: 27016501]
  148. Nat Metab. 2022 Feb;4(2):170-179 [PMID: 35210610]
  149. Semin Immunol. 2014 Feb;26(1):38-47 [PMID: 24602448]
  150. Eur J Neurosci. 2000 Apr;12(4):1241-52 [PMID: 10762353]
  151. World J Stem Cells. 2014 Nov 26;6(5):526-39 [PMID: 25426250]
  152. Front Cell Dev Biol. 2023 Feb 16;11:1104393 [PMID: 36875766]
  153. FEBS J. 2013 Sep;280(17):4131-48 [PMID: 23663276]
  154. Clin Exp Med. 2023 Nov;23(7):3719-3728 [PMID: 37310657]
  155. PLoS Curr. 2011 Apr 13;3:RRN1231 [PMID: 21826115]
  156. Sci Rep. 2022 Mar 19;12(1):4754 [PMID: 35306509]
  157. Neuropharmacology. 2016 Apr;103:27-43 [PMID: 26707655]
  158. NPJ Parkinsons Dis. 2022 Mar 15;8(1):24 [PMID: 35292674]
  159. Cell Immunol. 2018 May;327:77-82 [PMID: 29478949]
  160. Signal Transduct Target Ther. 2022 Mar 21;7(1):92 [PMID: 35314676]
  161. Stem Cell Investig. 2022 Apr 12;9:3 [PMID: 35450010]
  162. Mol Ther Oncolytics. 2023 Aug 15;30:238-253 [PMID: 37701849]
  163. Oncology. 2020;98(3):131-137 [PMID: 31958792]
  164. JAMA Neurol. 2016 Nov 01;73(11):1316-1324 [PMID: 27668667]
  165. Stem Cell Res Ther. 2021 Jul 13;12(1):400 [PMID: 34256857]

MeSH Term

Animals
Humans
Interleukin-6
Mesenchymal Stem Cell Transplantation
Mesenchymal Stem Cells
Nervous System Diseases
Neuroinflammatory Diseases
Signal Transduction

Chemicals

Interleukin-6
IL6 protein, human

Word Cloud

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