Endogenous galectin-3 expression levels modulate immune responses in galectin-3 transgenic mice

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Abstract

Galectin-3 (Gal-3), a β-galactoside-binding mammalian lectin, is involved in cancer progression and metastasis. However, there is an unmet need to identify the underlying mechanisms of cancer metastasis mediated by endogenous host galectin-3. Galectin-3 is also known to be an important regulator of immune responses. The present study was aimed at analysing how expression of endogenous galectin-3 regulates host immunity and lung metastasis in B16F10 murine melanoma model. Transgenic Gal-3+/− (hemizygous) and Gal-3−/− (null) mice exhibited decreased levels of Natural Killer (NK) cells and lower NK mediated cytotoxicity against YAC-1 tumor targets, compared to Gal-3+/+ (wild-type) mice. On stimulation, Gal-3+/− and Gal-3−/− mice splenocytes showed increased T cell proliferation than Gal-3+/+ mice. Intracellular calcium flux was found to be lower in activated T cells of Gal-3−/− mice as compared to T cells from Gal-3+/+ and Gal-3+/− mice. In Gal-3−/− mice, serum Th1, Th2 and Th17 cytokine levels were found to be lowest, exhibiting dysregulation of pro-inflammatory and anti-inflammatory cytokines balance. Marked decrease in serum IFN-γ levels and splenic IFN-γR1 (IFN-γ Receptor 1) expressing T and NK cell percentages were observed in Gal-3−/− mice. On recombinant IFN-γ treatment of splenocytes in vitro, Suppressor of Cytokine Signaling (SOCS) 1 and SOCS3 protein expression was higher in Gal-3−/− mice compared to that in Gal-3+/+ and Gal-3+/− mice; suggesting possible attenuation of Signal Transducer and Activator of Transcription (STAT) 1 mediated IFN-γ signaling in Gal-3−/− mice. The ability of B16F10 melanoma cells to form metastatic colonies in the lungs of Gal-3+/+ and Gal-3−/− mice remained comparable, whereas it was found to be reduced in Gal-3+/− mice. Our data indicates that complete absence of endogenous host galectin-3 facilitates lung metastasis of B16F10 cells in mice, which may be contributed by dysregulated immune responses resulting from decreased NK cytotoxicity, disturbed serum Th1, Th2, Th17 cytokine milieu, reduced serum IFN-γ levels and attenuation of splenic STAT1 mediated IFN-γ signalling in Gal-3−/− mice.

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