BackgroundInterstitial pneumonia in connective tissue diseases (CTD-IP) featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells (MSCs) may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders.MethodsLung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts (HLFs) from patients pathologically diagnosed with usual interstitial pneumonia (UIP) and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals (HBMSCs) on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro.ResultsHigher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell (Treg) level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of α-smooth muscle actin (α-SMA). The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis (IPF). HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked α-SMA activation in CTD-UIP HLFs through a TGF-β1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-β1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice.ConclusionsImpairment of TGF-β signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-β1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0319-y) contains supplementary material, which is available to authorized users.
The aberrant activation of the JAK2/STAT3 signaling in immature myeloid dendritic cells (DCs) is associated with immune tolerance and poor antitumor immunity. The objective of this study was to test the hypothesis that Cucurbitacin B (CuB), a selective inhibitor of JAK2/STAT3 signaling, could promote DC differentiation and improve antitumor immunity. Twelve patients with advanced lung cancers were treated orally with CuB daily for 7 consecutive days. The frequency of peripheral blood myeloid DCs and immature myeloid cells (imCs) in those patients and healthy controls was characterized longitudinally by flow cytometry. The effect of CuB on the differentiation of DCs and p53-specific T responses was evaluated in vitro. The percentages of Lin(-)DR(-)CD33(+) imCs and Lin(-)DR(+)CD33(+) DCs were significantly different between patients with lung cancers and healthy controls (1.55% vs. 0.82%, p=0.002; 0.60% vs. 1.90%, p=0.000). Treatment with CuB significantly increased the frequency of Lin(-)DR(+)CD33(+), but reduced the frequency of Lin(-)DR(-)CD33(+) in patients with lung cancers (p<0.05). Treatment with CuB induced the differentiation of DCs cocultured with tumor cells 16HBE/BPDE and enhanced the sensitivity of 16HBE/BPDE cells to p53-specific CTL by inhibiting the JAK2/STAT3 activation, but also enhancing the interferon-γ-related STAT1 activation in 16HBE/BPDE cells. CuB significantly reduced the frequency of imCs in patients with lung cancers and enhanced the effect of p53-specific CTL on tumor 16HBE/BPDE cells.
Our data suggest that increased expression of HMGA2 represents a possible new mechanism of myeloid differentiation blockage of leukaemia. Aberrant expression of HMGA2 may enhance HOXA9-dependent leukaemogenesis and myeloid leukaemia phenotype. Disturbance of the HMGA2-HOXA9 pathway is probably a therapeutic strategy in myeloid leukaemia.
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