TLR4 enhances TGF-β signaling and hepatic fibrosis

Seki, Ekihiro; Minicis, S. De; Österreicher, Christoph H.; Kluwe, Johannes; Osawa, Yosuke; Brenner, David A.; Schwabe, Robert F.

doi:10.1038/nm1663

Cited by 1,691 publications

(1,961 citation statements)

References 46 publications

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“…37,41 In fact, recent evidence shows the existence of a crosstalk between TLR and activin signal-transduction pathways, which, in the case between TGFb and TLR signaling, has been well documented. 42,43 Thus, activin A decreases the phosphorylation of extracellular signal-regulated kinase 1/2, p38, Jun N-terminal kinase, mitogen-activated protein kinases and the p65 subunit of NF-kB (nuclear factor kappa-light-chain enhancer of activated B cells), which are classical effectors of the TLR4/CD14/MD2 signaling in LPS-stimulated macrophages, leading to a reduced TNF-a and IL-8 production (Figure 1 (6), right panel). 44 Moreover, this effect was dependent on the maintenance of SH2-containing inositol 5¢-phosphatase levels, which were enhanced by (1) Activin A establishes a positive-feedback signal increasing ActRIIA on the cell surface through the expression of ARIP2, (2) upregulates the expression of MHC class II and costimulatory molecules, (3) induces nuclear translocation of NF-kB, (4) augments phagocytic activity and (5) promotes the secretion of cytokines, inflammatory mediators and matrix-metalloproteinase-2.…”

Section: Monocytesmentioning

confidence: 99%

When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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Activins and inhibins are members of the transforming growth factor-b superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation of hematopoiesis in the bone marrow under homeostatic and inflammatory conditions. Recent data provide a more comprehensive understanding about the role of activins/inhibins in the immune system. Novel findings included in this review point out the important requirement of activin/inhibin signaling to maintain the balance between homeostatic and inflammatory signals that are required for the optimal development and function of immune cells. The purpose of this review is to highlight the versatile nature of activins/inhibins as key regulators of both the innate and adaptive immune responses. Keywords: activin; inhibin; inflammation; immune cells; immunity; tolerance Activins and inhibins are members of the transforming growth factor-b (TGF-b) superfamily that were initially described as regulators of reproductive processes in mammals, and were first named after their positive and negative effect in the release of follicle-stimulating hormone from the pituitary gland, respectively. 1 These dimeric ligands have been shown to modulate a variety of cellular functions such as apoptosis, proliferation, differentiation, cellular migration, among others. 2,3 Activin A (bA/bA) is the best-characterized ligand of this subfamily, although there are other bioactive forms, activin B (bB/bB) and activin AB (bA/bB), which differ in their potency and cellular function. 4 Activin A is a molecule with pleiotropic functions, which shares with TGF-b the SMAD2/3 canonical signaling pathway (reviewed by Shi and Massague 5 ) but uses distinct type II (ActRIIs) and type I (ALK2, ALK4 and ALK7) receptors. [6][7][8][9] The biological function of activins can be blocked by follistatin (FS), a glycoprotein that binds activin A with high affinity, functioning as a ligand trap. 10 On the other hand, inhibins are heterodimers formed by uncommon a-and b-subunits and exist in two isoforms, inhibin A (a/bA) and B (a/bB). Inhibins have been shown to antagonize activinmediated functions by a mechanism that involves binding to b-glycan (TGFbRIII) and formation of a ternary complex with ActRIIs. As a consequence, activin type I receptors (ALK4 and ALK2) are excluded from the receptor complex, leading to the inhibition of SMADmediated signaling. 3,[11][12][13][14] Despite the fact that inhibins have been classically considered as activin antagonists, there is evidence showing that they do not always antagonize activin-mediated functions in several cell types, suggesting the existence of an independent inhibinmediated signaling pathway. 3 Compelling evidence has shown that activins also regulate various non-reproductive processes, such as mesoderm induction, liver proliferation, skin morphogenesis, erythropoiesis, bone formation, neu...

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Section: Monocytesmentioning

confidence: 99%

When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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“…HpSCs express α smooth muscle actin (α-SMA), the histological hallmark of myofibroblasts, and are thought to be the pivotal to the pathogenesis of liver fibrosis. As in other responses, Kupffer cells seem to be key cells, activating HpSCs by secretion of TGFβ, and bacterial products such as lipopolysaccharide (LPS) engage toll-like receptors on stellate cells, down-regulating the inhibitory TGFβ pseudoreceptor Bambi, allowing unrestricted activation of HpSCs by the Kupffer cells [113]. Apart from activated stellate cells, portal fibroblasts and hepatocytes/cholangiocytes undergoing epithelial-mesenchymal transition have been implicated in the fibrogenic response [112].…”

Section: Liver Fibrosismentioning

confidence: 99%

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

198

148

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The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.

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“…On a cellular level, the activation of liver-resident macrophages, traditionally called "Kupffer cells," and the vast infiltration of monocytes into the injured liver have been identified as major pathogenic factors (4). Because this pool of hepatic macrophages releases essential proinflammatory cytokines (e.g., TNF), they promote hepatocellular stress responses and lipid accumulation (5)(6)(7)(8). In addition, CD8 T cells endorse liver fibrosis via activating hepatic stellate cells (HSC) (9), whereas NK cells are capable of promoting HSC apoptosis and are thus considered antifibrotic (10,11).…”

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confidence: 99%

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Wehr

Baeck

Heymann

et al. 2013

The Journal of Immunology

215

186

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Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6+/gfp and Cxcr6gfp/gfp mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6−/− mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6−/− mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.

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TLR4 enhances TGF-β signaling and hepatic fibrosis

Cited by 1,691 publications

References 46 publications

When versatility matters: activins/inhibins as key regulators of immunity

When versatility matters: activins/inhibins as key regulators of immunity

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

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