Phenylmethimazole Suppresses dsRNA-Induced Cytotoxicity and Inflammatory Cytokines in Murine Pancreatic Beta Cells and Blocks Viral Acceleration of Type 1 Diabetes in NOD Mice
Abstract
:1. Introduction
2. Results and Discussion
2.1. C10 Protects Pancreatic Beta Cells from dsRNA-Induced Cytotoxicity
2.2. C10 Blocks dsRNA-Induced Upregulation of TLR3 Expression and Signaling Products in Pancreatic Beta Cells
Functional Gene Groupings/Gene Name | TC-6 cells | NIT-1 Cells | |||||||
---|---|---|---|---|---|---|---|---|---|
Pattern Recognition Receptors | pIC | pIC + DMSO | pIC + C10 | pIC | pIC + DMSO | pIC + C10 | |||
Toll-Like Receptor 1 | 5.78 | <5 | <5 | <5 | <5 | <5 | |||
Toll-Like Receptor 2 | 8.20 | <5 | <5 | 26.17 | 11.59 | <5 | |||
Toll-Like Receptor 3 | 66.7 | 23.2 | <5 | 176.0 | 64.2 | <5 | |||
Toll-Like Receptor 4 | 5.78 | <5 | <5 | <5 | <5 | <5 | |||
Toll-Like Receptor 6 | <5 | <5 | <5 | 22.24 | <5 | <5 | |||
Toll-Like Receptor 7 | 5.74 | <5 | <5 | <5 | <5 | <5 | |||
Toll-Like Receptor 8 | 5.74 | <5 | <5 | <5 | <5 | <5 |
Functional Gene Groupings/Gene Name | TC-6 cells | NIT-1 Cells | ||||
---|---|---|---|---|---|---|
pIC | pIC + DMSO | pIC + C10 | pIC | pIC + DMSO | pIC + C10 | |
TLR adaptor proteins | ||||||
Heat shock 70kDa protein 1A (Hspa1a) | <5 | <5 | <5 | 20.32 | <5 | 8.30 |
TICAM2 | <5 | <5 | <5 | 9.58 | 6.57 | <5 |
Transcription factors | ||||||
c-Fos | <5 | <5 | <5 | 5.45 | <5 | <5 |
c-Jun | <5 | <5 | <5 | 14.37 | <5 | <5 |
CCAAT/enhancer binding protein β (Cebpb) | <5 | <5 | <5 | 9.22 | <5 | <5 |
NF-κB pathway | ||||||
CCL2 | 21.50 | 22.25 | <5 | 172.45 | 30.70 | <5 |
CD80 | 6.03 | 6.69 | <5 | 40.22 | 20.97 | <5 |
CD86 | <5 | <5 | <5 | 68.12 | 35.38 | <5 |
Granulocyte macrophage colony-stimulating factor (Csf2) | <5 | <5 | <5 | 5.92 | <5 | <5 |
Granulocyte colony-stimulating factor (Csf3) | <5 | <5 | <5 | 6.80 | <5 | <5 |
IKKα (Chuk) | <5 | <5 | <5 | 5.37 | <5 | <5 |
IL-1α | <5 | <5 | <5 | 7.31 | <5 | <5 |
IL-2 | 5.78 | <5 | <5 | <5 | <5 | <5 |
IL-6 | 8.91 | 8.98 | <5 | 580.04 | 143.01 | <5 |
IL-6 Receptor α (IL-6ra) | <5 | <5 | <5 | 25.46 | <5 | <5 |
IL-10 | <5 | <5 | <5 | 57.68 | 22.24 | <5 |
IL-12A | 6.62 | <5 | <5 | 10.78 | 22.09 | <5 |
NF-κB2 | 8.52 | <5 | <5 | 22.86 | 16.56 | <5 |
IκBα (Nfkbia) | <5 | <5 | <5 | 13.50 | <5 | <5 |
IκBβ (Nfkbib) | <5 | <5 | <5 | 14.47 | <5 | <5 |
Prostaglandin-endoperoxide synthase 2 (Ptgs2) | <5 | <5 | <5 | 48.34 | 17.69 | <5 |
TNF-α | 5.78 | <5 | <5 | 26.72 | 6.70 | <5 |
TNF-β (Lta) | NS | <5 | <5 | 45.57 | 38.59 | <5 |
Tumor necrosis factor, alpha-induced protein 3 (Tnfaip3) | 7.87 | <5 | <5 | <5 | <5 | <5 |
IRF pathway | ||||||
IP-10 (CXCL10) | 189.49 | 74.85 | <5 | 543.07 | 141.53 | <5 |
IFN-β1 | 135.86 | 72.81 | <5 | 2778.33 | 196.04 | <5 |
IRF-1 | 6.85 | 6.32 | <5 | 12.04 | 11.24 | <5 |
Functional Gene Groupings/Gene Name | TC-6 Cells | NIT-1 Cells | ||||||
---|---|---|---|---|---|---|---|---|
pIC | pIC + DMSO | pIC + C10 | pIC | pIC + DMSO | pIC + C10 | |||
Chemokines | ||||||||
CCL2 | 13.60 | 6.96 | <5 | 160.12 | 25.05 | <5 | ||
CCL4 | 39.15 | 5.94 | <5 | 25.33 | 25.58 | <5 | ||
CCL5 | 320.9 | 112.21 | <5 | 1245.92 | 384.54 | <5 | ||
CCL7 | 18.2 | 14.42 | <5 | 107.49 | 91.90 | <5 | ||
CCL9 | <5 | <5 | <5 | 6.86 | <5 | <5 | ||
CCL12 | 8.76 | <5 | <5 | 19.95 | 8.80 | <5 | ||
CCL19 | <5 | <5 | <5 | 26.32 | 32.38 | 64.40 | ||
CCL20 | 183.67 | 54.19 | <5 | 76.27 | 43.17 | <5 | ||
CCL25 | 23.36 | 21.33 | <5 | <5 | <5 | <5 | ||
CXCL1 | 7.57 | <5 | <5 | <5 | <5 | <5 | ||
CXCL5 | 5.86 | <5 | <5 | <5 | 10.14 | <5 | ||
CXCL9 | 58.32 | 17.94 | <5 | 344.41 | 275.71 | <5 | ||
CXCL10 | 150.23 | 133.9 | <5 | 522.03 | 170.31 | <5 | ||
CXCL11 | <5 | <5 | <5 | 74.70 | 67.51 | <5 | ||
Chemokine receptors | ||||||||
CCR10 | 179.27 | 57.48 | <5 | <5 | <5 | <5 | ||
Cytokines | ||||||||
IL-1F6 | <5 | <5 | <5 | 38.94 | 15.97 | <5 | ||
IL-4 | 41.53 | 11.84 | <5 | <5 | <5 | <5 | ||
IL-10 | <5 | <5 | <5 | 28.11 | 10.87 | <5 | ||
IL-11 | 33.61 | 10.67 | <5 | 19.00 | 8.65 | <5 | ||
IL-15 | 139.68 | 43.26 | <5 | 36.45 | 35.19 | <5 | ||
Osteopontin (Spp1) | 18.33 | NS | <5 | <5 | <5 | <5 | ||
TGF-β1 | 62.51 | 20.32 | <5 | <5 | <5 | <5 | ||
TNF-α | <5 | <5 | <5 | 21.38 | 5.76 | <5 | ||
TNF-β (Lta) | <5 | <5 | <5 | 38.27 | 34.82 | <5 | ||
Lymphotoxin-β (Ltb) | 299.41 | 13.83 | <5 | <5 | <5 | <5 | ||
Cytokine receptors | ||||||||
Glycoprotein 130 (IL-6st) | 324.26 | 110.66 | <5 | <5 | <5 | <5 | ||
IL-1R2 | 21.27 | 5.82 | <5 | <5 | <5 | <5 | ||
IL-5Rα | 11.88 | <5 | <5 | <5 | <5 | <5 | ||
Tumor necrosis factor receptor superfamily 1B (Tnfrsf1b) | −23.65 | −62.47 | <5 | <5 | <5 | <5 | ||
Integrin β2 (Itgb) | <5 | <5 | <5 | 10.54 | <5 | <5 | ||
Other inflammatory genes | ||||||||
Caspase 1 (Casp1) | 17.52 | 6.06 | <5 | 15.98 | 7.02 | −6.15 |
2.3. C10 Attenuates Coxsackievirus B4 (CVB4) Acceleration of T1DM in Non-Obese Diabetic (NOD) Mice
3. Experimental
3.1. Reagents
3.2. Cell Culture and Transfections
3.3. Cellular Viability Assays
3.4. Quantitative Real Time PCR
3.5. Quantitative Real Time PCR Arrays
3.6. CXCL10 ELISA
3.7. NOD Mouse Experiment
4. Conclusions
Acknowledgments
References
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- Sample Availability: Samples of the compound (C10) are available from the Interthyr Corporation.
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McCall, K.D.; Schmerr, M.J.; Thuma, J.R.; James, C.B.L.; Courreges, M.C.; Benencia, F.; Malgor, R.; Schwartz, F.L. Phenylmethimazole Suppresses dsRNA-Induced Cytotoxicity and Inflammatory Cytokines in Murine Pancreatic Beta Cells and Blocks Viral Acceleration of Type 1 Diabetes in NOD Mice. Molecules 2013, 18, 3841-3858. https://doi.org/10.3390/molecules18043841
McCall KD, Schmerr MJ, Thuma JR, James CBL, Courreges MC, Benencia F, Malgor R, Schwartz FL. Phenylmethimazole Suppresses dsRNA-Induced Cytotoxicity and Inflammatory Cytokines in Murine Pancreatic Beta Cells and Blocks Viral Acceleration of Type 1 Diabetes in NOD Mice. Molecules. 2013; 18(4):3841-3858. https://doi.org/10.3390/molecules18043841
Chicago/Turabian StyleMcCall, Kelly D., Martin J. Schmerr, Jean R. Thuma, Calvin B. L. James, Maria C. Courreges, Fabian Benencia, Ramiro Malgor, and Frank L. Schwartz. 2013. "Phenylmethimazole Suppresses dsRNA-Induced Cytotoxicity and Inflammatory Cytokines in Murine Pancreatic Beta Cells and Blocks Viral Acceleration of Type 1 Diabetes in NOD Mice" Molecules 18, no. 4: 3841-3858. https://doi.org/10.3390/molecules18043841