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Interleukin-12 and interleukin-18 induce indoleamine 2,3-dioxygenase (IDO) activity in human osteosarcoma cell lines
Christian Liebau1, Axel W A Baltzer, Sebastian Schmidt
1Department of Orthopaedic Surgery, Ernst-Moritz-Arndt-University of Greifswald, Germany.
Purpose:
In this study we evaluated the ability of inducing activation of the enzyme indoleamine 2,3-dioxygenase (IDO) for the development of a new adjuvant therapy of osteosarcomas. The pathway that has described in the literature states that IDO activity is elevated by IFN-gamma. This mechanism is important because the increased IDO activation induces an intracellular degradation of the essential amino acid tryptophan and thereby activates apoptosis in human osteosarcoma cells.
Materials And Methods:
Four different well-established human osteosarcoma cell lines (MNNG/HOS, KHOS-240, HOS and MG-63) were investigated in vitro. Several cytokines were tested for their ability to induce IDO activity. However special emphasis was placed to evaluate the synergistic effects of Interleukin-12 (IL-12) in combination with Interleukin-18 (IL-18). In the first series of experiments IDO induction was investigated by direct application of the cytokines IFN-gamma, TNF-alpha, IL-12 and IL-18 in different concentrations. Secondly, the increase of IDO expression from osteosarcoma cell lines was analysed in the presence of activated lymphocytes with or without cytokine application.
Results:
Our results demonstrated that the combined application of IL-12 and IL-18 enhanced IDO activity in the human osteosarcoma cell lines HOS and MG-63, in the presence of activated lymphocytes. In the absence of activated lymphocytes, no significant enhancement could be detected. In all our experiments the increase in IDO expression was only partly inhibited by blocking INF-gamma.
Conclusion:
The presented study demonstrates that IL-12 and IL-18, or even more a combined application of both cytokines, induce IDO expression besides the known pathway via IFN-gamma. These mechanisms have been shown herein for the first time in human osteosacoma cell lines. Since IDO expression could still be shown after complete blocking of IFN-gamma, we conclude that at least a second pathway is responsible for inducing IDO activity. This is in contrast to the present knowledge about IDO activation.
Insights
Interleukin-12 (IL-12) and Interleukin-18 (IL-18) can activate indoleamine 2,3-dioxygenase (IDO) in osteosarcoma cells, offering a new therapeutic strategy. This activation occurs independently of interferon-gamma (IFN-gamma), suggesting novel treatment pathways.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Indoleamine 2,3-dioxygenase (IDO) plays a role in cancer immune evasion.
- IDO activation leads to tryptophan degradation and apoptosis in cancer cells.
- Current understanding suggests IFN-gamma is the primary inducer of IDO.
Purpose of the Study:
- To investigate the potential of novel cytokine combinations for inducing IDO activity in osteosarcoma.
- To explore alternative pathways for IDO activation beyond IFN-gamma.
- To evaluate IL-12 and IL-18 as potential adjuvant therapies for osteosarcomas.
Main Methods:
- In vitro analysis of four human osteosarcoma cell lines.
- Testing various cytokines (IFN-gamma, TNF-alpha, IL-12, IL-18) for IDO induction.
- Assessing synergistic effects of IL-12 and IL-18, particularly with activated lymphocytes.
Main Results:
- Combined IL-12 and IL-18 significantly enhanced IDO activity in HOS and MG-63 cells with activated lymphocytes.
- No significant IDO enhancement was observed in the absence of activated lymphocytes.
- Blocking IFN-gamma only partially inhibited the observed increase in IDO expression.
Conclusions:
- IL-12 and IL-18, especially in combination, induce IDO expression in human osteosarcoma cell lines.
- This induction occurs through mechanisms independent of, or in addition to, the known IFN-gamma pathway.
- The findings suggest a novel therapeutic approach for osteosarcoma by targeting IDO via IL-12 and IL-18.
