Interleukin-6 (IL-6)

A forum investigating the similarities between COVID-19 and fluoride poisoning, thyroid dysfunction and Gq/11 pathways.
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Interleukin-6 (IL-6)

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"There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications."

(Russell et al., 2020)

Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S, Van Hemelrijck M - "Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence" Ecancermedicalscience 14:1022 (2020)
doi: 10.3332/ecancer.2020.1022. PMID: 32256705; PMCID: PMC7105343
"Our study showed that high level of IL-6, CRP and hypertension were independent risk factors for assessing the severity of COVID-19. The risk model established upon IL-6, CRP and hypertension had the highest predictability in this study. Besides, IL-6 played a pivotal role in the severity of COVID-19 and had a potential value for monitoring the process of severe cases."

(Zhu et al, 2020)

Zhu Z, Cai T, Fan L, Lou K, Hua X, Huang Z, Gao G - "Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019" Int J Infect Dis 95:332-339 (2020). doi: 10.1016/j.ijid.2020.04.041. Epub ahead of print. PMID: 32334118; PMCID: PMC7195003.


Gao Y, Li T, Han M, Li X, Wu D, Xu Y, Zhu Y, Liu Y, Wang X, Wang L - "Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19" J Med Virol (2020) doi: 10.1002/jmv.25770. Epub ahead of print. PMID: 32181911.


Effects are dose- and time-dependent (i.e. Zhang et al., 2020). At low doses fluoride increases IL-6 levels, while at higher levels IL-6 levels are decreased.

"A marked increase in the mRNA level for IL-6 was observed already 2 h after exposure to 5 mM NaF, and presumably is a prerequisite for the subsequent increase of IL-6. The fluoride-induced effects on IL-6 and IL-8 release were strongly reduced by pretreatment with deferoxamine (an Al3+-chelator), and enhanced by addition of Al3+. This indicates that an AlF4-- complex, a known activator of GTP-binding proteins, is involved in fluoride-induced IL-6 and IL-8 responses in A549 cells."

(Refsnes et al., 1999)

Refsnes M, Becher R, Lâg M, Skuland T, Schwarze PE - "Fluoride-induced interleukin-6 and interleukin-8 synthesis in human epithelial lung cells" Hum Exp Toxicol 18(11):645-52 (1999) doi: 10.1191/096032799678839572. PMID: 10602388.

Liu J, Wang HW, Zhao WP, Li XT, Lin L, Zhou BH - "Induction of pathological changes and impaired expression of cytokines in developing female rat spleen after chronic excess fluoride exposure" Toxicol Ind Health (2019) 35(1):43-52

Wu P, Sun Z, Lv X, Pei X, Manthari RK, Wang J - "Fluoride Induces Autoimmune Orchitis Involved with Enhanced IL-17A Secretion in Mice Testis" J Agric Food Chem. 67(48):13333-13343 (2019)

Wang HW, Liu J, Zhao WP, Zhang ZH, Li SQ, Li SH, Zhu SQ, Zhou BH - "Effect of Fluoride on Small Intestine Morphology and Serum Cytokine Contents in Rats" Biol Trace Elem Res 189(2):511-518 (2019)

Ma Y, Niu R, Sun Z, Wang J, Luo G, Zhang J, Wang J - "Inflammatory responses induced by fluoride and arsenic at toxic concentration in rabbit aorta" Arch Toxicol. 86(6):849-56 (2012)
"We found that fluoride and arsenic alone or combined increased the expression of VCAM-1, P-sel, MCP-1, IL-8, and IL-6 at the RNA and protein levels."

Zhang Y, Zhou BH, Tan PP, Chen Y, Miao CY, Wang HW - " Key Role of Pro-inflammatory Cytokines in the Toxic Effect of Fluoride on Hepa1-6 Cells" Biol Trace Elem Res 197(1):115-122 (2020)
"The content of IL-6 remarkably increased with increasing fluoride concentrations up to 2 mmol/L, and then markedly decreased at 3, 4, and 5 mmol/L fluoride; the decreasing trend of IL-6 content under high fluoride exposure is consistent with the decrease in Hepa1-6 cell viability observed at the same concentration."

de Cássia Alves Nunes R, Chiba FY, Pereira AG, Pereira RF, de Lima Coutinho Mattera MS, Ervolino E, Louzada MJ, Buzalaf MA, Silva CA, Sumida DH - "Effect of Sodium Fluoride on Bone Biomechanical and Histomorphometric Parameters and on Insulin Signaling and Insulin Sensitivity in Ovariectomized Rats" Biol Trace Elem Res 173(1):144-53 (2016)

G q/11:
"We conclude that extracellular acidification stimulates IL-6 production and Ca(2+) mobilization through proton-sensing OGR1 receptors/G(q/11) proteins in human airway smooth muscle cells."
(Ichimonji et al., 2010)

Ichimonji I, Tomura H, Mogi C, Sato K, Aoki H, Hisada T, Dobashi K, Ishizuka T, Mori M, Okajima F - "Extracellular acidification stimulates IL-6 production and Ca(2+) mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells" Am J Physiol Lung Cell Mol Physiol 299(4):L567-77 (2010)
doi: 10.1152/ajplung.00415.2009. Epub 2010 Jul 23. PMID: 20656891
"These results suggest that UTP-induced IL-6 production is in part mediated via phosphorylation of ERK through G(q/11)/IP(3)/[Ca(2+)](i) and transactivation of the EGF receptor...."
(Kobayashi et al., 2006)

Kobayashi D, Ohkubo S, Nakahata N. - "Contribution of extracellular signal-regulated kinase to UTP-induced interleukin-6 biosynthesis in HaCaT keratinocytes" J Pharmacol Sci 102(4):368-76 (2006)
doi: 10.1254/jphs.fp0060669. Epub 2006 Nov 28. PMID: 17130674

Abbott KL, Loss JR 2nd, Robida AM, Murphy TJ - "Evidence that Galpha(q)-coupled receptor-induced interleukin-6 mRNA in vascular smooth muscle cells involves the nuclear factor of activated T cells" Mol Pharmacol 58(5):946-53 (2000) doi: 10.1124/mol.58.5.946. PMID: 11040041

Others - Fluoride:

Refsnes M, Schwarze PE, Holme JA, Låg M - "Fluoride-induced apoptosis in human epithelial lung cells (A549 cells): role of different G protein-linked signal systems" Hum Exp Toxicol 22(3):111-23 (2003) doi: 10.1191/0960327103ht322oa PMID: 12723891

Refsnes M, Thrane EV, Låg M, Thoresen GH, Schwarze PE - "Mechanisms in fluoride-induced interleukin-8 synthesis in human lung epithelial cells" Toxicology 167(2):145-58 (2001) doi: 10.1016/s0300-483x(01)00448-6 PMID: 11567778

Refsnes M, Skuland T, Schwarze PE, Øvrevik J, Låg M - "Fluoride-induced IL-8 release in human epithelial lung cells: relationship to EGF-receptor-, SRC- and MAP-kinase activation" Toxicol Appl Pharmacol 227(1):56-67 (2008) doi: 10.1016/j.taap.2007.09.022. Epub 2007 Oct 3. PMID: 17996917

Ridley W, Matsuoka M - "Fluoride-induced cyclooxygenase-2 expression and prostaglandin E2 production in A549 human pulmonary epithelial cells" Toxicol Lett 188(3):180-5 (2009) doi: 10.1016/j.toxlet.2009.04.007. Epub 2009 Apr 17.
PMID: 19376214

Kawase T, Ishikawa I, Orikasa M, Suzuki A - "Aluminum enhances the stimulatory effect of NaF on prostaglandin E2 synthesis in a clonal osteoblast-like cell line, MOB 3-4, in vitro" J Biochem 106(1):8-10 (1989)
doi: 10.1093/oxfordjournals.jbchem.a122824.
PMID: 2777755


Contreras-Jurado C, Alonso-Merino E, Saiz-Ladera C, Valiño AJ, Regadera J, Alemany S, Aranda A - "The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia" Sci Rep 6:30990 (2016)
doi: 10.1038/srep30990. PMID: 27484112; PMCID: PMC4971531.

Hodkinson CF, Simpson EE, Beattie JH, O'Connor JM, Campbell DJ, Strain JJ, Wallace JM - "Preliminary evidence of immune function modulation by thyroid hormones in healthy men and women aged 55-70 years" J Endocrinol 202(1):55-63 (2009) doi: 10.1677/JOE-08-0488. Epub 2009 Apr 27. PubMed PMID:19398496 ... 2/1/55.xml

Bartalena L, Brogioni S, Grasso L, Rago T, Vitti P, Pinchera A, Martino E - "Interleukin-6: a marker of thyroid-destructive processes?" J Clin Endocrinol Metab. 79(5):1424-7 (1994) doi: 10.1210/jcem.79.5.7962338. PMID: 7962338 ... 24/2649325


Raychaudhuri N, Fernando R, Smith TJ - "Thyrotropin regulates IL-6 expression in CD34+ fibrocytes: clear delineation of its cAMP-independent actions" PLoS One. 8(9):e75100 (2013)
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Posts: 3314
Joined: Tue Jan 18, 2005 10:25 pm

Re: Interleukin-6 (IL-6)

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Konca Degertekin C, Turhan Iyidir O, Aktas Yılmaz B, Elbeg S, Pasaoglu OT, Pasaoglu H, Cakır N, Arslan M - "RANKL/Osteoprotegerin System and Bone Turnover in Hashimoto Thyroiditis" Calcif Tissue Int 99(4):365-72 (2016)
"TSH was negatively correlated with IL-6"
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