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Role of histamine in natural killer cell-mediated resistance against tumor cells
K Hellstrand1, A Asea, S Hermodsson
1Department of Clinical Virology, University of Göteborg, Sweden.
Abstract:
The formation of lung metastases by i.v.-injected B16 melanoma (F1 and F10 strain) cells in Swiss albino, C57BL/6, and BALB/c mice was reduced by a single dose of histamine given 24 h before tumor cell inoculation. The antimetastatic effect of histamine was specifically mediated by histamine H2-receptors (H2R): it was blocked by the H2R antagonist ranitidine and mimicked by dimaprit, a specific H2R agonist but not by an H2R-inactive structural analog of this compound, nor-dimaprit, or the H1R agonist 2-thiazolyl-ethylamide. A single dose of any of the H2R antagonists ranitidine, tiotidine, famotidine, or cimetidine drastically augmented metastasis. Effects of H2R-interactive compounds on B16 metastasis required intact NK cells, as judged by the inability of histamine or ranitidine to affect B16 metastasis after NK cell depletion in vivo using antibodies to asialo-GM1. NK-cell-mediated lysis of YAC-1 lymphoma cells in vivo was enhanced by histamine and reduced by ranitidine within 4 h after inoculation of tumor cells. The antimetastatic effect of IL-2 was potentiated by histamine; in some experiments, combined treatment with a low dose of IL-2 (6000 U/kg) and histamine completely eliminated metastasis, whereas concomitant treatment with ranitidine abrogated antimetastatic effects of IL-2; animals treated with ranitidine and IL-2 displayed the same level of enhanced metastasis as those treated with ranitidine alone. The presented data are suggestive of an earlier unrecognized role for histamine in NK cell-mediated resistance against metastatic tumor cells.
Insights
Histamine reduces lung metastasis by activating histamine H2-receptors (H2R) and enhancing natural killer (NK) cell activity. Blocking H2R with antagonists increases metastasis, suggesting histamine
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Metastasis formation is a critical determinant of cancer patient survival.
- The role of histamine in cancer progression and immune response is not fully understood.
- Natural Killer (NK) cells are crucial for early defense against tumor metastasis.
Purpose of the Study:
- To investigate the role of histamine and its receptors in the formation of lung metastases.
- To elucidate the involvement of NK cells in histamine's antimetastatic effects.
- To explore the potential synergy between histamine and Interleukin-2 (IL-2) in cancer therapy.
Main Methods:
- Administered B16 melanoma cells intravenously to mice to induce lung metastases.
- Treated mice with histamine, H2R agonists/antagonists, or NK cell-depleting antibodies.
- Assessed metastasis formation and NK cell-mediated cytotoxicity in vivo.
Main Results:
- Histamine administration significantly reduced lung metastasis formation.
- The antimetastatic effect was mediated by histamine H2-receptors (H2R) and required intact NK cells.
- H2R antagonists increased metastasis, while histamine enhanced NK cell activity and potentiated IL-2's antimetastatic effects.
Conclusions:
- Histamine plays a previously unrecognized role in NK cell-mediated resistance against metastatic tumor cells.
- Targeting histamine H2R may represent a novel therapeutic strategy to enhance anti-metastatic immunity.
- Combined therapy with histamine and IL-2 shows promise for eliminating metastasis.