Toll-Like Receptor 4 Mediates Alcohol-Induced Steatohepatitis Through Bone Marrow-Derived and Endogenous Liver Cells in Mice

Abstract Evidences accumulated that immature dendritic cell (iDC) could inhibit alloantigen-specific T cell responses and prolong the survival time of allografts. However, the tolerogenic properties of these iDCs were often unstable or inconsistent because of in vivo maturation, such as lipopolysaccharide (LPS) stimulating. Toll-like receptor 4(TLR4) has been reported to act as a receptor for LPS and LPS can stimulate iDC to mature DC (mDC) via TLR4 signal transduction pathway. In this study, we investigated the effects of transforming growth factor β1 on murine bone marrow derived DCs. Murine bone marrow cells were cultured with GM-CSF and TGF-β1 to generate TGF-β1 treated DCs (TGFβ-DCs). Compared to iDCs cultured by GM-CSF alone, the TGFβ-DCs had no significant alterations in ultrastructure after LPS stimulation. Surface expression of CD80, CD86, CD40, MHC-II were inhibited by addition of TGF-β1, especially in CD80, CD86 (p<0.05). Furthermore, the iDCs were sensitive to further maturation in response to LPS by showing increased levels of MHC class II, CD80, CD86 and CD40. In marked contrast, TGF-β1 prevented this LPS-mediated maturation and maintained the cells in the immature state, with low levels of surface costimulatory molecules expression. Using BrdU incorporation method, after 96 h mix lymphocyte reaction, TGFβ-DCs had weaker allogeneic stimulating capacity than iDCs. Importantly, LPS stimulating strongly promoted the allostimulatory capacity of iDCs, whereas only slightly affected TGFβ-DCs. TGFβ-DCs also showed decreased IL-12p70 production and impaired NF-κB activation after LPS stimulation. We also found the expression of TLR4 mRNA on TGFβ-DCs was weaker than that on iDCs by RT-PCR. Moreover, the results of flow cytometry revealed the positive expression percentages of TLR4/MD2 complex on iDCs and TGFβ-DCs were (51.8±3.89% vs. 15.7±4.13%, p<0.01) and the mean fluorescence intensities (MFIs) were (2.37±0.26 vs. 1.36±0.17, p<0.05). These results agreed with previous findings that TGFβ-DCs responded weakly to LPS. In summary, TGFβ-DC is resistant to maturation stimulus (LPS) and might have some correlation with the down-modulation of TLR4 expression.

Download Full-text

Tenascin‑C promotes the migration of bone marrow stem cells via toll‑like receptor 4‑mediated signaling pathways: MAPK, AKT and Wnt

Molecular Medicine Reports ◽

10.3892/mmr.2018.8855 ◽

2018 ◽

Author(s):

Huaiyu Ding ◽

Mingyu Jin ◽

Dai Liu ◽

Shujing Wang ◽

Jianing Zhang ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Signaling Pathways ◽

Bone Marrow Stem Cells ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Tenascin C

Download Full-text

Functional differences of Toll‐like receptor 4 in osteogenesis, adipogenesis and chondrogenesis in human bone marrow‐derived mesenchymal stem cells

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16506 ◽

2021 ◽

Author(s):

Fatemeh Khodabandehloo ◽

Reza Aflatoonian ◽

Zahra Zandieh ◽

Farzad Rajaei ◽

Forugh‐Azam Sayahpour ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Functional Differences

Download Full-text

Toll-Like Receptor 4/Stem Cell Antigen 1 Signaling Promotes Hematopoietic Precursor Cell Commitment to Granulocyte Development during the Granulopoietic Response to Escherichia coli Bacteremia

Infection and Immunity ◽

10.1128/iai.01280-12 ◽

2013 ◽

Vol 81 (6) ◽

pp. 2197-2205 ◽

Cited By ~ 17

Author(s):

Xin Shi ◽

Robert W. Siggins ◽

William L. Stanford ◽

John N. Melvan ◽

Marc D. Basson ◽

...

Keyword(s):

Escherichia Coli ◽

Bone Marrow ◽

Stem Cell ◽

Precursor Cell ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Content Type ◽

E Coli ◽

Hematopoietic Precursor

ABSTRACTIn response to severe bacterial infection, bone marrow hematopoietic activity shifts toward promoting granulopoiesis. The underlying cell signaling mechanisms remain obscure. To study the role of Toll-like receptor 4 (TLR4)/stem cell antigen-1 (Sca-1) signaling in this process, bacteremia was induced in mice by intravenous injection ofEscherichia coli. A subgroup of animals also received intravenous 5-bromo-2-deoxyuridine (BrdU). In a separate set of experiments, bone marrow lineage-negative (lin−) stem cell growth factor receptor-positive (c-kit+) Sca-1−cells containing primarily common myeloid progenitors were culturedin vitrowithout or withE. colilipopolysaccharide (LPS). In genotypic background control mice, bacteremia significantly upregulated Sca-1 expression by lin−c-kit+cells, as reflected by a marked increase in BrdU-negative lin−c-kit+Sca-1+cells in the bone marrow. In mice with the TLR4 gene deletion, this bacteremia-evoked Sca-1 response was blocked.In vitro, LPS induced a dose-dependent increase in Sca-1 expression by cultured marrow lin−c-kit+Sca-1−cells. LPS-induced upregulation of Sca-1 expression was regulated at the transcriptional level. Inhibition of c-Jun N-terminal kinase/stress-activated protein kinase (JNK) activity with the specific inhibitor SP600125 suppressed LPS-induced upregulation of Sca-1 expression by marrow lin−c-kit+Sca-1−cells. Engagement of Sca-1 with anti-Sca-1 antibodies enhanced the expression of Sfpi1 spleen focus-forming virus (SFFV) proviral integration 1 (PU.1) in marrow lin−c-kit+Sca-1−cells cultured with LPS. Sca-1 null mice failed to maintain the marrow pool of granulopoietic cells following bacteremia. These results demonstrate that TLR4/Sca-1 signaling plays an important role in the regulation of hematopoietic precursor cell programming and their enhancement of granulocyte lineage commitment in response toE. colibacteremia.

Download Full-text