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IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis.

Maurer M, Bougoin S, Feferman T, Frenkian M, Bismuth J, Mouly V, Clairac G, Tzartos S, Fadel E, Eymard B, Fuchs S, Souroujon MC, Berrih-Aknin S - Acta Neuropathol Commun (2015)

Bottom Line: Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin).Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

View Article: PubMed Central - PubMed

Affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, Paris, F-75013, France. sonia.berrih-aknin@upmc.fr.

ABSTRACT

Introduction: Anti-acetylcholine receptor (AChR) autoantibodies target muscles in spontaneous human myasthenia gravis (MG) and its induced experimental autoimmune model MG (EAMG). The aim of this study was to identify novel functional mechanisms occurring in the muscle pathology of myasthenia.

Results: A transcriptome analysis performed on muscle tissue from MG patients (compared with healthy controls) and from EAMG rats (compared with control rats) revealed a deregulation of genes associated with the Interleukin-6 (IL-6) and Insulin-Like Growth Factor 1 (IGF-1) pathways in both humans and rats. The expression of IL-6 and its receptor IL-6R transcripts was found to be altered in muscles of EAMG rats and mice compared with control animals. In muscle biopsies from MG patients, IL-6 protein level was higher than in control muscles. Using cultures of human muscle cells, we evaluated the effects of anti-AChR antibodies on IL-6 production and on the phosphorylation of Protein Kinase B (PKB/Akt). Most MG sera and some monoclonal anti-AChR antibodies induced a significant increase in IL-6 production by human muscle cells. Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.

Conclusions: Anti-AChR antibodies alter IL-6 production by muscle cells, suggesting a putative novel functional mechanism of action for the anti-AChR antibodies. IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin). Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

No MeSH data available.


Related in: MedlinePlus

Mechanisms of action of mAb 198. (A) Comparison of the proliferation of human muscle cells in the presence of anti-AChR antibodies or isotype control using CFSE. Fluorescence geometric means (GM) decreased with time but did not exhibit any differences when the cells were treated with anti-AChR mAb or isotype control (3 μ/ml). (B) Kinetics of IL-6 production by LHCNM2 after stimulation with mAb 198 anti-AChR antibody is represented in black, and mRNA expression is represented in grey. IL-6 production was measured by ELISA assays and normalized to isotype controls (n = 4 for each group and time). mRNA expression was measured by Q-RT-PCR and was normalized to GAPDH (n = 2 for each group and time). Mean ± SEM is represented.
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Fig5: Mechanisms of action of mAb 198. (A) Comparison of the proliferation of human muscle cells in the presence of anti-AChR antibodies or isotype control using CFSE. Fluorescence geometric means (GM) decreased with time but did not exhibit any differences when the cells were treated with anti-AChR mAb or isotype control (3 μ/ml). (B) Kinetics of IL-6 production by LHCNM2 after stimulation with mAb 198 anti-AChR antibody is represented in black, and mRNA expression is represented in grey. IL-6 production was measured by ELISA assays and normalized to isotype controls (n = 4 for each group and time). mRNA expression was measured by Q-RT-PCR and was normalized to GAPDH (n = 2 for each group and time). Mean ± SEM is represented.

Mentions: To determine whether the increased IL-6 production was due to an increased cell number induced by anti-AChR antibodies, we compared the proliferation of human muscle cells in the presence of anti-AChR antibodies or isotype controls using CFSE labeling. There was no difference in the CFSE fluorescence intensity whether the cells were cultured in the presence of anti-AChR or isotype-matched antibodies (Figure 5A). These results suggest that the anti-AChR antibodies do not induce muscle cell proliferation, emphasizing that the increased production of IL-6 was not due to an increased number of cells.Figure 5


IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis.

Maurer M, Bougoin S, Feferman T, Frenkian M, Bismuth J, Mouly V, Clairac G, Tzartos S, Fadel E, Eymard B, Fuchs S, Souroujon MC, Berrih-Aknin S - Acta Neuropathol Commun (2015)

Mechanisms of action of mAb 198. (A) Comparison of the proliferation of human muscle cells in the presence of anti-AChR antibodies or isotype control using CFSE. Fluorescence geometric means (GM) decreased with time but did not exhibit any differences when the cells were treated with anti-AChR mAb or isotype control (3 μ/ml). (B) Kinetics of IL-6 production by LHCNM2 after stimulation with mAb 198 anti-AChR antibody is represented in black, and mRNA expression is represented in grey. IL-6 production was measured by ELISA assays and normalized to isotype controls (n = 4 for each group and time). mRNA expression was measured by Q-RT-PCR and was normalized to GAPDH (n = 2 for each group and time). Mean ± SEM is represented.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308930&req=5

Fig5: Mechanisms of action of mAb 198. (A) Comparison of the proliferation of human muscle cells in the presence of anti-AChR antibodies or isotype control using CFSE. Fluorescence geometric means (GM) decreased with time but did not exhibit any differences when the cells were treated with anti-AChR mAb or isotype control (3 μ/ml). (B) Kinetics of IL-6 production by LHCNM2 after stimulation with mAb 198 anti-AChR antibody is represented in black, and mRNA expression is represented in grey. IL-6 production was measured by ELISA assays and normalized to isotype controls (n = 4 for each group and time). mRNA expression was measured by Q-RT-PCR and was normalized to GAPDH (n = 2 for each group and time). Mean ± SEM is represented.
Mentions: To determine whether the increased IL-6 production was due to an increased cell number induced by anti-AChR antibodies, we compared the proliferation of human muscle cells in the presence of anti-AChR antibodies or isotype controls using CFSE labeling. There was no difference in the CFSE fluorescence intensity whether the cells were cultured in the presence of anti-AChR or isotype-matched antibodies (Figure 5A). These results suggest that the anti-AChR antibodies do not induce muscle cell proliferation, emphasizing that the increased production of IL-6 was not due to an increased number of cells.Figure 5

Bottom Line: Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin).Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

View Article: PubMed Central - PubMed

Affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, Paris, F-75013, France. sonia.berrih-aknin@upmc.fr.

ABSTRACT

Introduction: Anti-acetylcholine receptor (AChR) autoantibodies target muscles in spontaneous human myasthenia gravis (MG) and its induced experimental autoimmune model MG (EAMG). The aim of this study was to identify novel functional mechanisms occurring in the muscle pathology of myasthenia.

Results: A transcriptome analysis performed on muscle tissue from MG patients (compared with healthy controls) and from EAMG rats (compared with control rats) revealed a deregulation of genes associated with the Interleukin-6 (IL-6) and Insulin-Like Growth Factor 1 (IGF-1) pathways in both humans and rats. The expression of IL-6 and its receptor IL-6R transcripts was found to be altered in muscles of EAMG rats and mice compared with control animals. In muscle biopsies from MG patients, IL-6 protein level was higher than in control muscles. Using cultures of human muscle cells, we evaluated the effects of anti-AChR antibodies on IL-6 production and on the phosphorylation of Protein Kinase B (PKB/Akt). Most MG sera and some monoclonal anti-AChR antibodies induced a significant increase in IL-6 production by human muscle cells. Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.

Conclusions: Anti-AChR antibodies alter IL-6 production by muscle cells, suggesting a putative novel functional mechanism of action for the anti-AChR antibodies. IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin). Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

No MeSH data available.


Related in: MedlinePlus