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Membrane-associated interleukin 1 alpha as a mediator of tumor cell killing by human blood monocytes fixed with
13rd Department of Internal Medicine, University of Tokushima School of Medicine, Japan.
Abstract:
Human blood monocytes isolated by centrifugal elutriation from healthy donors were tested for ability to produce membrane-associated antitumor monokine(s) in response to activation stimuli such as various types of interferon (IFN) and/or synthetic desmethyl muramyl dipeptide (norMDP). IFNs (alpha, beta, and gamma) and norMDP rendered blood monocytes cytotoxic to allogeneic A375 melanoma cells, as assayed by measuring release of [125I]iododeoxyuridine in 72 h. When monocytes were treated with any type of IFN for 16 h, and then fixed with paraformaldehyde, they did not show cytotoxicity to A375 cells, but when they were fixed after treatment with norMDP or lipopolysaccharide they showed significant cytotoxicity to A375 melanoma cells. This membrane-associated antitumor monokine induced by the synergistic actions of suboptimal concentrations of IFN-gamma and norMDP, was cytotoxic to HT-29 colon cancer cells as well as A375 melanoma cells, but not to actinomycin D-treated L-929 cells. The fixed monocyte-mediated cytotoxicity against A375 melanoma cells was completely inhibited by a specific anti-interleukin 1 alpha antiserum, but not by a specific anti-interleukin 1 beta antiserum or monoclonal anti-TNF antibody. These results suggest that membrane-associated interleukin 1 alpha is involved through cell-to-cell contact in the host defense mechanism against cancer.
Insights
Human monocytes activated by interferons (IFN) and norMDP exhibit antitumor activity against melanoma cells. Membrane-associated interleukin 1 alpha plays a key role in this cancer defense mechanism.
Area of Science:
- Immunology
- Cancer Biology
- Cell Biology
Background:
- Human blood monocytes are key immune cells involved in host defense.
- Cancer immunotherapy aims to harness immune cells to fight malignancies.
- Monokines, cytokines produced by monocytes, can exhibit anti-tumor properties.
Purpose of the Study:
- To investigate the potential of human monocytes to produce membrane-associated antitumor monokines.
- To identify the stimuli that activate monocytes for anti-cancer activity.
- To elucidate the specific monokine involved in monocyte-mediated tumor cell killing.
Main Methods:
- Human monocytes were isolated using centrifugal elutriation.
- Monocytes were activated with interferons (IFN-alpha, beta, gamma) and/or synthetic norMDP.
- Cytotoxicity was assessed against A375 melanoma and HT-29 colon cancer cells.
- Monocyte-mediated cytotoxicity was analyzed using specific antibody inhibition assays.
Main Results:
- IFNs and norMDP induced monocyte cytotoxicity against A375 melanoma cells.
- Fixed monocytes treated with norMDP or lipopolysaccharide showed significant cytotoxicity.
- Synergistic action of IFN-gamma and norMDP induced a membrane-associated monokine cytotoxic to melanoma and colon cancer cells.
- This cytotoxicity was specifically inhibited by anti-interleukin 1 alpha antiserum.
Conclusions:
- Membrane-associated interleukin 1 alpha is induced in monocytes by IFN-gamma and norMDP.
- Interleukin 1 alpha mediates monocyte-dependent anti-tumor activity through cell-to-cell contact.
- This finding suggests a role for interleukin 1 alpha in host defense against cancer.