Top

Journal of Translational Medicine

Published in:

Open Access 01-12-2021 | Fatigue | Research

The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP₂ and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients

Authors: Natalie Eaton-Fitch, Hélène Cabanas, Stanley du Preez, Donald Staines, Sonya Marshall-Gradisnik

Published in: Journal of Translational Medicine | Issue 1/2021

Abstract

Background

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS. Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology. This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP₂). The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated.

Methods

NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP₂ of ME/CFS patients and HC. Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured.

Results

Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP₂ and actin in HC. Co-localisation of TRPM3 with PIP₂ in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2. A significant increase in co-localisation of TRPM3 with PIP₂ was reported following overnight treatment with ononetin within ME/CFS patients and between groups. Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients.

Conclusion

Significant changes in co-localisation suggest PIP₂-dependent TRPM3 function may be impaired in ME/CFS patients. Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca²⁺ influx and PIP₂. While IL-2R responds to IL-2 binding in vitro, Ca²⁺ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients.

Available only for authorised users

Cortes Rivera M, Mastronardi C, Silva-Aldana CT, Arcos-Burgos M, Lidbury BA. Myalgic encephalomyelitis/chronic fatigue syndrome: a comprehensive review. Diagnostics. 2019. https://doi.org/10.3390/diagnostics9030091.CrossRefPubMedPubMedCentral

Carruthers BM, Jain AK, Meirleir KLD, Peterson DL, Klimas NG, Lerner AM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome. J Chronic Fatigue Syndr. 2003;11:7–115. https://doi.org/10.1300/J092v11n01_02.CrossRef

Carruthers BM, van de Sande MI, Meirleir KLD, Klimas NG, Broderick G, Mitchell T, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270:327–38. https://doi.org/10.1111/j.1365-2796.2011.02428.x.CrossRefPubMedPubMedCentral

Fukuda K. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994;121:953. https://doi.org/10.7326/0003-4819-121-12-199412150-00009.CrossRefPubMed

Cabanas H, Muraki K, Eaton N, Balinas C, Staines D, Marshall-Gradisnik S. Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. Mol Med. 2018;24:44. https://doi.org/10.1186/s10020-018-0046-1.CrossRefPubMedPubMedCentral

Marshall-Gradisnik S, Huth T, Chacko A, Johnston S, Smith P, Staines D. Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome. Appl Clin Genet. 2016;9:39–47. https://doi.org/10.2147/TACG.S99405.CrossRefPubMedPubMedCentral

Nguyen T, Staines D, Nilius B, Smith P, Marshall-Gradisnik S. Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients. Biol Res. 2016;49:27. https://doi.org/10.1186/s40659-016-0087-2.CrossRefPubMedPubMedCentral

Balinas C, Cabanas H, Staines D, Marshall-Gradisnik S. Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2019. https://doi.org/10.1186/s12967-019-02155-4.CrossRefPubMedPubMedCentral

Montell C, Birnbaumer L, Flockerzi V. The TRP channels, a remarkably functional family. Cell. 2002;108:595–8. https://doi.org/10.1016/s0092-8674(02)00670-0.CrossRefPubMed

10.

Nilius B, Owsianik G. Transient receptor potential channelopathies. Pflugers Arch. 2010;460:437–50. https://doi.org/10.1007/s00424-010-0788-2.CrossRefPubMed

11.

Kim J-B. Channelopathies. Korean. J Pediatr. 2014;57:1–18. https://doi.org/10.3345/kjp.2014.57.1.1.CrossRef

12.

Nguyen T, Johnston S, Clarke L, Smith P, Staines D, Marshall-Gradisnik S. Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels. Clin Exp Immunol. 2017;187:284–93. https://doi.org/10.1111/cei.12882.CrossRefPubMed

13.

Cabanas H, Muraki K, Balinas C, Eaton-Fitch N, Staines D, Marshall-Gradisnik S. Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients. Mol Med. 2019;25:14. https://doi.org/10.1186/s10020-019-0083-4.CrossRefPubMedPubMedCentral

14.

Cabanas H, Muraki K, Staines D, Marshall-Gradisnik S. Naltrexone restores impaired transient receptor potential melastatin 3 ion channel function in natural killer cells from myalgic encephalomyelitis/chronic fatigue syndrome patients. Front Immunol. 2019. https://doi.org/10.3389/fimmu.2019.02545.CrossRefPubMedPubMedCentral

15.

Oberwinkler J, Lis A, Giehl KM, Flockerzi V, Philipp SE. Alternative splicing switches the divalent cation selectivity of TRPM3 channels. J Biol Chem. 2005;280:22540–8. https://doi.org/10.1074/jbc.M503092200.CrossRefPubMed

16.

Grimm C, Kraft R, Sauerbruch S, Schultz G, Harteneck C. Molecular and functional characterization of the melastatin-related cation channel TRPM3. J Biol Chem. 2003;278:21493–501. https://doi.org/10.1074/jbc.M300945200.CrossRefPubMed

17.

Przibilla J, Dembla S, Rizun O, Lis A, Jung M, Oberwinkler J, et al. Ca2+-dependent regulation and binding of calmodulin to multiple sites of Transient Receptor Potential Melastatin 3 (TRPM3) ion channels. Cell Calcium. 2018;73:40–52. https://doi.org/10.1016/j.ceca.2018.03.005.CrossRefPubMed

18.

Holendova B, Grycova L, Jirku M, Teisinger J. PtdIns(4,5)P2 interacts with CaM binding domains on TRPM3 N-terminus. Channels. 2012;6:479–82. https://doi.org/10.4161/chan.22177.CrossRefPubMedPubMedCentral

19.

Patapoutian A, Peier AM, Story GM, Viswanath V. ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat Rev Neurosci. 2003;4:529–39. https://doi.org/10.1038/nrn1141.CrossRefPubMed

20.

Smith CC, Gibbs TT, Farb DH. Pregnenolone sulfate as a modulator of synaptic plasticity. Psychopharmacology. 2014;231:3537–56. https://doi.org/10.1007/s00213-014-3643-x.CrossRefPubMedPubMedCentral

21.

Wagner TFJ, Loch S, Lambert S, Straub I, Mannebach S, Mathar I, et al. Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells. Nat Cell Biol. 2008;10:1421–30. https://doi.org/10.1038/ncb1801.CrossRefPubMed

22.

Straub I, Mohr F, Stab J, Konrad M, Philipp SE, Oberwinkler J, et al. Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM3. Br J Pharmacol. 2013;168:1835–50. https://doi.org/10.1111/bph.12076.CrossRefPubMedPubMedCentral

23.

Tóth BI, Konrad M, Ghosh D, Mohr F, Halaszovich CR, Leitner MG, et al. Regulation of the transient receptor potential channel TRPM3 by phosphoinositides. J Gen Physiol. 2015;146:51–63. https://doi.org/10.1085/jgp.201411339.CrossRefPubMedPubMedCentral

24.

Czech MP. PIP2 and PIP3: complex roles at the cell surface. Cell. 2000;100:603–6. https://doi.org/10.1016/s0092-8674(00)80696-0.CrossRefPubMed

25.

Hao J-J, Liu Y, Kruhlak M, Debell KE, Rellahan BL, Shaw S. Phospholipase C–mediated hydrolysis of PIP2 releases ERM proteins from lymphocyte membrane. J Cell Biol. 2009;184:451–62. https://doi.org/10.1083/jcb.200807047.CrossRefPubMedPubMedCentral

26.

Berridge MJ, Bootman MD, Roderick HL. Calcium: calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4:517–29. https://doi.org/10.1038/nrm1155.CrossRefPubMed

27.

Cao C, Zakharian E, Borbiro I, Rohacs T. Interplay between calmodulin and phosphatidylinositol 4,5-bisphosphate in Ca2+-induced inactivation of Transient Receptor Potential Vanilloid 6 channels. J Biol Chem. 2013. https://doi.org/10.1074/jbc.M112.409482.CrossRefPubMedPubMedCentral

28.

Tobelaim WS, Dvir M, Lebel G, Cui M, Buki T, Peretz A, et al. Ca2+-Calmodulin and PIP2 interactions at the proximal C-terminus of Kv7 channels. Channels. 2017;11:686–95. https://doi.org/10.1080/19336950.2017.1388478.CrossRefPubMedPubMedCentral

29.

Oh-hora M, Rao A. Calcium signaling in lymphocytes. Curr Opin Immunol. 2008;20:250–8. https://doi.org/10.1016/j.coi.2008.04.004.CrossRefPubMedPubMedCentral

30.

Kloc M, Kubiak JZ, Li XC, Ghobrial RM. The newly found functions of MTOC in immunological response. J Leukoc Biol. 2014;95:417–30. https://doi.org/10.1189/jlb.0813468.CrossRefPubMed

31.

Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003;4:552–65. https://doi.org/10.1038/nrm1150.CrossRefPubMed

32.

Berridge MJ. Calcium signalling remodelling and disease. Biochem Soc Trans. 2012;40:297–309. https://doi.org/10.1042/BST20110766.CrossRefPubMed

33.

Mills GB, Cheung RK, Grinstein S, Gelfand EW. Interleukin 2-induced lymphocyte proliferation is independent of increases in cytosolic-free calcium concentrations. J Immunol. 1985;134:2431–5.PubMed

34.

Gasteiger G, Hemmers S, Firth MA, Le-Floc’h A, Huse M, Sun JC, et al. IL-2–dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J Exp Med. 2013;210:1167–78. https://doi.org/10.1084/jem.20122462.CrossRefPubMedPubMedCentral

35.

Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017;15:23. https://doi.org/10.1186/s12964-017-0177-y.CrossRefPubMedPubMedCentral

36.

Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol. 1990;28:1403–10.CrossRef

37.

Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J, et al. Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med. 2011;9:81. https://doi.org/10.1186/1479-5876-9-81.CrossRefPubMedPubMedCentral

38.

Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, et al. Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. J Transl Med. 2015. https://doi.org/10.1186/s12967-015-0653-3.CrossRefPubMedPubMedCentral

39.

Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, et al. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS ONE. 2010;5: e10817. https://doi.org/10.1371/journal.pone.0010817.CrossRefPubMedPubMedCentral

40.

Maher KJ, Klimas NG, Fletcher MA. Chronic fatigue syndrome is associated with diminished intracellular perforin. Clin Exp Immunol. 2005;142:505–11. https://doi.org/10.1111/j.1365-2249.2005.02935.x.CrossRefPubMedPubMedCentral

41.

Eaton-Fitch N, du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S. A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis/chronic fatigue syndrome. Syst Rev. 2019;8:279. https://doi.org/10.1186/s13643-019-1202-6.CrossRefPubMedPubMedCentral

42.

Nuttall FQ. Body Mass Index. Nutr Today. 2015;50:117–28. https://doi.org/10.1097/NT.0000000000000092.CrossRefPubMedPubMedCentral

43.

Ware JE. SF-36 health survey update. Spine. 2000;25:3130–9. https://doi.org/10.1097/00007632-200012150-00008.CrossRefPubMed

44.

WHO | WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). WHO n.d. http://www.who.int/classifications/icf/whodasii/en/. Accessed 8 May 2020.

45.

Panda SK, Ravindran B. Isolation of human PBMCs. Bio-Protoc 2013. https://doi.org/10.21769/BioProtoc.323.

46.

Aubry JP, Blaecke A, Lecoanet-Henchoz S, Jeannin P, Herbault N, Caron G, et al. Annexin V used for measuring apoptosis in the early events of cellular cytotoxicity. Cytometry. 1999;37:197–204. https://doi.org/10.1002/(sici)1097-0320(19991101)37:3%3c197::aid-cyto6%3e3.0.co;2-l.CrossRefPubMed

47.

Frühwald J, Camacho Londoño J, Dembla S, Mannebach S, Lis A, Drews A, et al. Alternative splicing of a protein domain indispensable for function of transient receptor potential melastatin 3 (TRPM3) ion channels. J Biol Chem. 2012;287:36663–72. https://doi.org/10.1074/jbc.M112.396663.CrossRefPubMedPubMedCentral

48.

Ferrandiz-Huertas C, Mathivanan S, Wolf CJ, Devesa I, Ferrer-Montiel A. Trafficking of ThermoTRP Channels. Membranes. 2014;4:525–64. https://doi.org/10.3390/membranes4030525.CrossRefPubMedPubMedCentral

49.

Kavalali ET. SNARE interactions in membrane trafficking: a perspective from mammalian central synapses. BioEssays News Rev Mol Cell Dev Biol. 2002;24:926–36. https://doi.org/10.1002/bies.10165.CrossRef

50.

Wedel BJ, Vazquez G, McKay RR, Bird GSJ, Putney JW. A Calmodulin/Inositol 1,4,5-trisphosphate (IP3) receptor-binding region targets TRPC3 to the plasma membrane in a calmodulin/IP3 receptor-independent process. J Biol Chem. 2003;278:25758–65. https://doi.org/10.1074/jbc.M303890200.CrossRefPubMed

51.

Baukrowitz T, Schulte U, Oliver D, Herlitze S, Krauter T, Tucker SJ, et al. PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science. 1998;282:1141–4. https://doi.org/10.1126/science.282.5391.1141.CrossRefPubMed

52.

Sui JL, Petit-Jacques J, Logothetis DE. Activation of the atrial KACh channel by the βγ subunits of G proteins or intracellular Na+ ions depends on the presence of phosphatidylinositol phosphates. Proc Natl Acad Sci. 1998;95:1307–12. https://doi.org/10.1073/pnas.95.3.1307.CrossRefPubMedPubMedCentral

53.

Tobelaim WS, Dvir M, Lebel G, Cui M, Buki T, Peretz A, et al. Competition of calcified calmodulin N lobe and PIP2 to an LQT mutation site in Kv71 channel. Proc Natl Acad Sci. 2017;114:E869–78. https://doi.org/10.1073/pnas.1612622114.CrossRefPubMedPubMedCentral

54.

Nilius B, Owsianik G, Voets T. Transient receptor potential channels meet phosphoinositides. EMBO J. 2008;27:2809–16. https://doi.org/10.1038/emboj.2008.217.CrossRefPubMedPubMedCentral

55.

Rohacs T, Nilius B. Regulation of transient receptor potential (TRP) channels by phosphoinositides. Pflüg Arch - Eur J Physiol. 2007;455:157–68. https://doi.org/10.1007/s00424-007-0275-6.CrossRef

56.

Gees M, Colsoul B, Nilius B. The role of transient receptor potential cation channels in Ca2+ signaling. Cold Spring Harb Perspect Biol. 2010. https://doi.org/10.1101/cshperspect.a003962.CrossRefPubMedPubMedCentral

57.

Shaw PJ, Feske S. Regulation of lymphocyte function by ORAI and STIM proteins in infection and autoimmunity. J Physiol. 2012;590:4157–67. https://doi.org/10.1113/jphysiol.2012.233221.CrossRefPubMedPubMedCentral

58.

Colonna M. Below the NK-cell surface: PIP2. Blood. 2008;111:3916. https://doi.org/10.1182/blood-2008-01-131516.CrossRefPubMedPubMedCentral

59.

Uchida K, Demirkhanyan L, Asuthkar S, Cohen A, Tominaga M, Zakharian E. Stimulation-dependent gating of TRPM3 channel in planar lipid bilayers. FASEB J. 2016;30:1306–16. https://doi.org/10.1096/fj.15-281576.CrossRefPubMed

60.

Ng L-T, Ko H-H, Lu T-M. Potential antioxidants and tyrosinase inhibitors from synthetic polyphenolic deoxybenzoins. Bioorg Med Chem. 2009;17:4360–6. https://doi.org/10.1016/j.bmc.2009.05.019.CrossRefPubMed

61.

Lotzová E, Savary CA, Herberman RB. Induction of NK cell activity against fresh human leukemia in culture with interleukin 2. J Immunol Baltim Md. 1950;1987(138):2718–27.

62.

Biron CA, Young HA, Kasaian MT. Interleukin 2-induced proliferation of murine natural killer cells in vivo. J Exp Med. 1990;171:173–88.CrossRef

63.

Lanier LL. Natural killer cell receptor signaling. Curr Opin Immunol. 2003;15:308–14. https://doi.org/10.1016/s0952-7915(03)00039-6.CrossRefPubMed

64.

Tomasello E, Bléry M, Vély F, Vivier E. Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells. Semin Immunol. 2000;12:139–47. https://doi.org/10.1006/smim.2000.0216.CrossRefPubMed

65.

Bryceson YT, Chiang SCC, Darmanin S, Fauriat C, Schlums H, Theorell J, et al. Molecular mechanisms of natural killer cell activation. J Innate Immun. 2011;3:216–26. https://doi.org/10.1159/000325265.CrossRefPubMed

66.

Ross SH, Rollings C, Anderson KE, Hawkins PT, Stephens LR, Cantrell DA. Phosphoproteomic analyses of interleukin 2 signaling reveal integrated JAK kinase-dependent and -independent networks in CD8+ T cells. Immunity. 2016;45:685–700. https://doi.org/10.1016/j.immuni.2016.07.022.CrossRefPubMedPubMedCentral

67.

Wu Y, Tian Z, Wei H. Developmental and functional control of natural killer cells by cytokines. Front Immunol. 2017. https://doi.org/10.3389/fimmu.2017.00930.CrossRefPubMedPubMedCentral

68.

Fan MY, Turka LA. Immunometabolism and PI(3)k signaling as a link between IL-2, foxp3 expression, and suppressor function in regulatory T cells. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.00069.CrossRefPubMedPubMedCentral

69.

Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36:320–8. https://doi.org/10.1016/j.tibs.2011.03.006.CrossRefPubMedPubMedCentral

70.

Yu T-K, Caudell EG, Smid C, Grimm EA. IL-2 activation of NK cells: involvement of MKK1/2/ERK but not p38 kinase pathway. J Immunol. 2000;164:6244–51. https://doi.org/10.4049/jimmunol.164.12.6244.CrossRefPubMed

71.

Najafov A, Shpiro N, Alessi D. Akt is efficiently activated by PIF-pocket- and PtdIns(3,4,5)P3-dependent mechanisms leading to resistance to PDK1 inhibitors. Biochem J. 2012. https://doi.org/10.1042/BJ20121287.CrossRefPubMed

72.

Huth TK, Staines D, Marshall-Gradisnik S. ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56dimCD16+ and CD56brightCD16dim/− natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. J Transl Med. 2016. https://doi.org/10.1186/s12967-016-0859-z.CrossRefPubMedPubMedCentral

73.

Mandarano AH, Maya J, Giloteaux L, Peterson DL, Maynard M, Gottschalk CG, et al. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest. 2020;130:1491–505. https://doi.org/10.1172/JCI132185.CrossRefPubMedPubMedCentral

74.

Nguyen T, Staines D, Johnston S, Marshall-Gradisnik S. Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: a preliminary investigation. Asian Pac J Allergy Immunol 2019;37:102–8. https://doi.org/10.12932/AP-011117-0188.

75.

Huth TK, Brenu EW, Nguyen T, Hardcastle SL, Staines D, Marshall-Gradisnik. Characterization of natural killer cell phenotypes in chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Cell Immunol 2014. https://doi.org/10.4172/2155-9899.1000223.

76.

Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, Johnston S, et al. Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis. Int Immunol. 2014;26:233–42. https://doi.org/10.1093/intimm/dxt068.CrossRefPubMed

77.

Morris G, Maes M. Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses. 2012;79:607–13. https://doi.org/10.1016/j.mehy.2012.07.034.CrossRefPubMed

78.

Bohuslav J, Kravchenko VV, Parry GC, Erlich JH, Gerondakis S, Mackman N, et al. Regulation of an essential innate immune response by the p50 subunit of NF-kappaB. J Clin Invest. 1998;102:1645–52. https://doi.org/10.1172/JCI3877.CrossRefPubMedPubMedCentral

79.

Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010;24:1209–17. https://doi.org/10.1016/j.bbi.2010.04.012.CrossRefPubMedPubMedCentral

80.

Brenu EW, van Driel ML, Staines DR, Ashton KJ, Hardcastle SL, Keane J, et al. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2012;10:88. https://doi.org/10.1186/1479-5876-10-88.CrossRefPubMedPubMedCentral

81.

Blundell S, Ray KK, Buckland M, White PD. Chronic fatigue syndrome and circulating cytokines: a systematic review. Brain Behav Immun. 2015;50:186–95. https://doi.org/10.1016/j.bbi.2015.07.004.CrossRefPubMed

82.

Saito S, Uozumi N. Calcium-regulated phosphorylation systems controlling uptake and balance of plant nutrients. Front Plant Sci. 2020. https://doi.org/10.3389/fpls.2020.00044.CrossRefPubMedPubMedCentral

83.

Qu B, Al-Ansary D, Kummerow C, Hoth M, Schwarz EC. ORAI-mediated calcium influx in T cell proliferation, apoptosis and tolerance. Cell Calcium. 2011;50:261–9. https://doi.org/10.1016/j.ceca.2011.05.015.CrossRefPubMed

Title: The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients
Authors: Natalie Eaton-Fitch
Hélène Cabanas
Stanley du Preez
Donald Staines
Sonya Marshall-Gradisnik
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Fatigue
Published in: Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-021-02974-4

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Establishment and evaluation of a rat model of extracorporeal membrane oxygenation (ECMO) thrombosis using a 3D-printed mock-oxygenator

Correction to: M2 macrophage-derived exosomal microRNAs inhibit cell migration and invasion in gliomas through PI3K/AKT/mTOR signaling pathway

A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation

Gender-specific associations between polymorphisms of the circadian gene RORA and cutaneous melanoma susceptibility

Cytotoxic lymphocytes-related gene ITK from a systematic CRISPR screen could predict prognosis of ovarian cancer patients with distant metastasis

FGFR2 alteration as a potential therapeutic target in poorly cohesive gastric carcinoma

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage