Transforming growth factor beta type 1 (TGF-β) and hypoxia-inducible factor 1 (HIF-1) transcription complex as master regulators of the immunosuppressive protein galectin-9 expression in human cancer and embryonic cells

High Mobility Group Box 1 (HMGB1) Induces Toll-Like Receptor 4-Mediated Production of the Immunosuppressive Protein Galectin-9 in Human Cancer Cells

“…TGF-b secreted by TLR4-expressing cancer cells (in our case THP-1 human AML cells), displays autocrine/paracrine activities, and thus acts on the malignant cells which have produced it. As a result, TGF-b induces galectin-9 production by these cells in a Smad3-dependent manner, the effect which has recently been reported (9) and confirmed in the present study. Galectin-9 subsequently displays immunosuppressive activities on cytotoxic and helper T cells in the tumour microenvironment as well as on NK cells (10,17).…”

“…Interestingly, TLR4 has recently been shown to mediate TGF-b production when activated by lipopolysaccharide (LPS), its pathogen-associated ligand, and some endogenous stimuli such as hyaluronic acid (25,26). It was also demonstrated that HMGB1-induced activation of TGF-b production in TLR4expressing cells takes place through the activator protein 1 (AP-1) transcription factor and its upstream pathway (9). HMGB1 displays TLR4 ligand properties and could act in TLR4-expressing cells similarly to that observed for LPS (6,9).…”

“…It was also demonstrated that HMGB1-induced activation of TGF-b production in TLR4expressing cells takes place through the activator protein 1 (AP-1) transcription factor and its upstream pathway (9). HMGB1 displays TLR4 ligand properties and could act in TLR4-expressing cells similarly to that observed for LPS (6,9). An additional factor which could mediate HMGB1-induced TGF-b expression in TLR4 expressing cells could be the hypoxia-inducible factor 1 (HIF-1) transcription complex, which is upregulated by TLR4-mediated downstream signalling (24).…”

“…Our recent work also suggested that, in Toll-like receptor 4 (TLR4)-expressing cells, HMGB1 induces the production and secretion of transforming growth factor beta type 1 (TGF-b) (9). TGF-b displays both autocrine and paracrine activities and, through the transcription factor Smad3, induces expression of galectin-9, an immunosuppressive protein which impairs the anti-cancer activities of natural killer and cytotoxic T cells (9,10). Galectin-9 is known as a so-called "tandem protein" which contains two ligand/sugar-binding domains fused together by a linker peptide.…”

“…Through these receptors HMGB1 in its immunogenic form could trigger both pro-inflammatory and pro-angiogenic responses (6). Our recent work also suggested that, in Toll-like receptor 4 (TLR4)-expressing cells, HMGB1 induces the production and secretion of transforming growth factor beta type 1 (TGF-b) (9). TGF-b displays both autocrine and paracrine activities and, through the transcription factor Smad3, induces expression of galectin-9, an immunosuppressive protein which impairs the anti-cancer activities of natural killer and cytotoxic T cells (9,10).…”