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Effect of calmodulin antagonists on the interferon system: induction and action of interferons
H Y Lin1, P J Davis, F B Davis
1Department of Microbiology, State University of New York, Buffalo 14214.
Abstract:
Synthesis of interferon (IFN) in response to Sendai virus and the development of the resulting antiviral state were studied in human (BG-9) and murine (L-929) fibroblast cell cultures in the presence of the calmodulin antagonists, trifluoperazine (TFP) and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). Compared to control cultures, 16-fold and 8-fold more IFN was formed in human and murine cells, respectively, when 10 microM TFP was present in the medium for 24 h prior to IFN induction with Sendai virus. W-7 did not affect IFN production in human cells, but enhanced it in L-929 cells by 4- to 8-fold. TFP inhibited the antiviral state induced by homologous IFN in the two cell systems, and at 20 microM, there was a 3,000-fold increase in vesicular stomatitis virus (VSV) yield. It also reduced the maintenance of the antiviral state in human cells. In contrast, W-7 had no effect on the development of the antiviral state in either of the two cell systems. Thus, calcium-calmodulin dependent cellular processes are involved in both induction of IFN and its action. The several patterns response to TFP and W-7 may reflect different ligand-binding sites on calmodulin.
Insights
Calcium-calmodulin pathways regulate interferon (IFN) production and antiviral state development. Calmodulin antagonists like trifluoperazine (TFP) significantly boosted IFN synthesis and impaired antiviral responses.
Area of Science:
- Immunology
- Cell Biology
- Virology
Background:
- Interferon (IFN) synthesis and the establishment of antiviral states are crucial host defense mechanisms against viral infections.
- Calmodulin, a key calcium-binding protein, is implicated in various cellular signaling pathways, but its specific role in IFN induction and action requires further elucidation.
Purpose of the Study:
- To investigate the involvement of calcium-calmodulin dependent processes in the induction of interferon (IFN) and the development of the antiviral state.
- To assess the effects of specific calmodulin antagonists, trifluoperazine (TFP) and W-7, on IFN production and antiviral activity in human and murine fibroblast cell cultures.
Main Methods:
- Human (BG-9) and murine (L-929) fibroblast cell cultures were treated with calmodulin antagonists trifluoperazine (TFP) and W-7.
- IFN induction was achieved using Sendai virus, and its production was quantified.
- The development and maintenance of the antiviral state were assessed by measuring vesicular stomatitis virus (VSV) yield in response to homologous IFN.
Main Results:
- Trifluoperazine (TFP) significantly enhanced IFN production in both human (16-fold) and murine (8-fold) cells.
- W-7 enhanced IFN production in murine cells (4- to 8-fold) but had no effect in human cells.
- TFP inhibited the development and maintenance of the antiviral state, leading to a 3,000-fold increase in VSV yield at 20 microM.
- W-7 did not affect the antiviral state in either cell system.
Conclusions:
- Calcium-calmodulin dependent cellular processes play a significant role in both the induction of IFN and the establishment of the antiviral state.
- The differential responses to TFP and W-7 suggest distinct calmodulin-binding sites or downstream signaling pathways involved in IFN regulation.
- These findings highlight the complex interplay between calcium signaling and antiviral immunity.