Galectin-3 exerts cytokine-like regulatory actions through the JAK-STAT pathway.
Galectin-3, a β-galactoside-binding lectin, has been proposed to have multifaceted functions in various pathophysiological conditions. However, the characteristics of galectin-3 and its molecular mechanisms of action are still largely unknown. In this study, we show that galectin-3 exerts cytokine-like regulatory actions in rat and mouse brain-resident immune cells. Both the expression of galectin-3 and its secretion into the extracellular compartment were significantly enhanced in glia under IFN-γ-stimulated, inflamed conditions. After exposure to galectin-3, glial cells produced high levels of proinflammatory mediators and exhibited activated properties. Notably, within minutes after exposure to galectin-3, JAK2 and STAT1, STAT3, and STAT5 showed considerable enhancement of tyrosine phosphorylation; thereafter, downstream events of STAT signaling were also significantly enhanced. Treatment of the cells with pharmacological inhibitors of JAK2 reduced the galectin-3-stimulated increases of inflammatory mediators. Using IFN-γ receptor 1-deficient mice, we further found that IFN-γR 1 might be required for galectin-3-dependent activation of the JAK-STAT cascade. However, galectin-3 significantly induced phosphorylation of STATs in glial cells from IFN-γ-deficient mice, suggesting that IFN-γ does not mediate activation of STATs. Collectively, our findings suggest that galectin-3 acts as an endogenous danger signaling molecule under pathological conditions in the brain, providing a potential explanation for the molecular basis of galectin-3-associated pathological events.
Jeon
Sae-Bom
SB
Immune and Cell Therapy Branch, National Cancer Center, Goyang, Korea.
Yoon
Hee Jung
HJ
Chang
Chi Young
CY
Koh
Han Seok
HS
Jeon
Seong-Ho
SH
Park
Eun Jung
EJ
D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D037502:Galectin 3 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology; D053614:Janus Kinase 2 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D000096743:Interferon gamma Receptor
D016207:Cytokines; D037502:Galectin 3; D018836:Inflammation Mediators; D007371:Interferon-gamma; D053614:Janus Kinase 2; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000096743:Interferon gamma Receptor; C485095:Lgals3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse