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Inflammatory Adipokines Decrease Expression of Two High Molecular Weight Isoforms of Tropomyosin Similar to the
Stuart A Savill1, Helen F Leitch1, John N Harvey1,2
1Betsi Cadwaladr University Health Board, Croesnewydd Road, Wrexham, United Kingdom.
Abstract:
Cardiovascular disease and cancer are increased in Type 2 diabetes. TPM1 and TPM4 genes encode proteins associated with cardiovascular and neoplastic disease. High (HMW) and low (LMW) molecular weight isoforms from TPM1 and TPM4 are altered in several cancer cells and the 3'UTR of TPM1 mRNA is tumour suppressive. Leukocytes influence cardiovascular and neoplastic disease by immunosurveillance for cancer and by chronic inflammation in Type 2 diabetes and cardiovascular disease. The aim was to determine changes in expression of isoforms from TPM1 and TPM4 genes in leukocytes from Type 2 diabetic patients and to use the leukocyte cell line THP1 to identify possible mediators of changes in the patients. Gene expression was determined by RT-qPCR. In diabetes, expression of HMW isoforms from TPM1 were markedly decreased (0.55 v 1.00; p = 0.019) but HMW isoforms from TPM4 were not significantly different (0.76 v 1.00; p = 0.205). Within individual variance in expression of HMW isoforms was very high. The change in expression in HMW isoforms from TPM1 and TPM4 was replicated in THP1 cells treated with 1 ng/ml TNFα (0.10 and 0.12 v 1.00 respectively) or 10 ng/ml IL-1α (0.17 and 0.14 v 1.00 respectively). Increased insulin or glucose concentrations had no substantial effects on TPM1 or TPM4 expression. Decreased TPM1 mRNA resulted in decreases in HMW protein levels. Expression of HMW isoforms from TPM1 is decreased in Type 2 diabetes. This is probably due to increased levels of inflammatory cytokines TNFα and IL-1α in Type 2 diabetes. Lower levels of TPM1 mRNA reduce tumour suppression and could contribute to increased cancer risk in Type 2 diabetes. Decreased HMW tropomyosin isoforms are associated with cancer. Decreased HMW isoforms give rise to cells that are more plastic, motile, invasive and prone to dedifferentiation resulting in leukocytes that are more invasive but less functionally effective.
Insights
In Type 2 diabetes, high molecular weight (HMW) tropomyosin 1 (TPM1) isoforms in leukocytes are decreased, potentially increasing cancer risk. Inflammatory cytokines likely mediate this change, impacting leukocyte function.
Area of Science:
- Molecular biology
- Immunology
- Endocrinology
Background:
- Type 2 diabetes is linked to increased cardiovascular disease and cancer risk.
- Tropomyosin (TPM) genes (TPM1, TPM4) encode proteins implicated in cardiovascular and neoplastic diseases.
- Leukocytes play roles in immunosurveillance and inflammation, relevant to Type 2 diabetes complications.
Purpose of the Study:
- To investigate changes in TPM1 and TPM4 gene expression in leukocytes of Type 2 diabetic patients.
- To utilize the THP1 leukocyte cell line to identify potential mediators of observed gene expression changes.
Main Methods:
- Gene expression analysis using quantitative reverse transcription polymerase chain reaction (RT-qPCR).
- Treatment of THP1 cells with tumor necrosis factor-alpha (TNFα) and interleukin-1 alpha (IL-1α).
- Assessment of insulin and glucose concentration effects on TPM gene expression.
Main Results:
- Expression of high molecular weight (HMW) TPM1 isoforms was significantly decreased in Type 2 diabetic leukocytes (p = 0.019).
- HMW TPM4 isoform expression showed no significant difference in Type 2 diabetes (p = 0.205).
- TNFα and IL-1α treatments in THP1 cells replicated the decrease in HMW TPM1 and TPM4 isoform expression.
Conclusions:
- HMW TPM1 isoform expression is reduced in Type 2 diabetes, likely due to elevated inflammatory cytokines TNFα and IL-1α.
- Reduced TPM1 mRNA levels may impair tumor suppression, contributing to cancer risk in Type 2 diabetes.
- Decreased HMW tropomyosin isoforms are associated with increased leukocyte invasiveness and reduced functional effectiveness, linking to cancer and cardiovascular disease.
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