ABSTRACT
OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy worldwide, with a high mortality. The prognosis of OSCC remains unsatisfactory; the dysregulated immune system plays an important role in the pathogenesis of OSCC. Myeloid-derived suppressor cells (MDSCs) have been identified as immune-suppressive cells in multiple tumor types. The aim of this study was to clarify the underlying immunoregulatory mechanism of MDSC in patients with OSCC. MATERIALS AND METHODS: Flow cytometry was used to analyze the phenotype of MDSC among peripheral blood mononuclear cells (PBMCs) from patients with OSCC and healthy control subjects. The correlation between MDSC frequency and the disease index of patients with OSCC was evaluated. T cell proliferation experiment was used to evaluate the immunosuppressive function of MDSC. RESULTS: Patients with OSCC exhibited significantly higher levels of PMN-MDSCs than did healthy controls. In the co-culture assay, T cell proliferation and IFN-γ production were abrogated by the addition of PMN-MDSCs in a dose-dependent manner. The levels of reactive oxygen species were higher for PMN-MDSCs derived from patients with OSCC than for those from normal individuals. p-STAT3 levels, a key activator of MDSCs, was higher in OSCC-related PMN-MDSCs than in those from healthy controls. Both of these effects were reversed by NAC (an ROS inhibitor) and JSI-124 (a p-STAT3 inhibitor). Finally, PMN-MDSC levels were positively related to histological differentiation, nodal metastasis, and recurrence. CONCLUSION: PMN-MDSCs were elevated in OSCC patients, with strong immune-suppressive effects via p-STAT3/reactive oxygen species, providing a new direction for therapeutic strategies.
Subject(s)
Mouth Neoplasms/immunology , Myeloid-Derived Suppressor Cells/immunology , Squamous Cell Carcinoma of Head and Neck/immunology , T-Lymphocytes/immunology , Acetylcysteine/pharmacology , Adult , Aged , Case-Control Studies , Cell Proliferation/drug effects , Cell Separation , Cells, Cultured , Coculture Techniques , Female , Flow Cytometry , Healthy Volunteers , Humans , Lymphocyte Activation/drug effects , Male , Middle Aged , Mouth Neoplasms/blood , Mouth Neoplasms/pathology , Myeloid-Derived Suppressor Cells/metabolism , Primary Cell Culture , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , Squamous Cell Carcinoma of Head and Neck/blood , Squamous Cell Carcinoma of Head and Neck/pathology , T-Lymphocytes/metabolism , Triterpenes/pharmacology , Young AdultABSTRACT
BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. The dysregulated immune system plays an important role in the pathogenesis of AS. Myeloid-derived suppressor cells (MDSCs) play a key immunoregulatory role in autoimmune arthritis. The aim of this study was to clarify the underlying immunoregulatory mechanism of MDSCs in patients with AS. METHODS: Flow cytometry was used to analyze the phenotype of MDSCs among peripheral blood mononuclear cells (PBMCs) from 46 patients with AS and 46 healthy control subjects. The correlation between MDSC frequency and the disease index of patients with AS was evaluated. A T cell proliferation experiment was used to evaluate the immunosuppressive function of MDSCs. RESULTS: Polymorphonuclear (PMN) and monocytic (M)-MDSCs were significantly elevated in the PBMCs of patients with AS, when compared with levels in healthy controls. Additionally, M-MDSC levels correlated positively with the clinical index of AS, including the Bath ankylosing spondylitis disease activity index (BASDAI) score, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. M-MDSCs derived from patients with AS suppressed T cell responses, and this effect was dependent on the induction of arginase-I. Furthermore, AS-derived M-MDSCs showed high levels of phosphorylated STAT3. Stattic, a STAT3-specific inhibitor, and STAT3-targeted siRNA abrogated the immunosuppressive function of M-MDSCs. Inhibition of STAT3 signaling also resulted in decreased arginase-I activity. CONCLUSIONS: STAT3/arginase-I signaling plays an important role in both the expansion and activation of M-MDSCs in patients with AS. This information may be beneficial in developing novel therapeutic strategies for preventing AS.
Subject(s)
Arginase/metabolism , Myeloid-Derived Suppressor Cells/immunology , STAT3 Transcription Factor/metabolism , Spondylitis, Ankylosing/immunology , Adult , Female , Humans , Male , Myeloid-Derived Suppressor Cells/metabolism , Signal Transduction/immunology , Spondylitis, Ankylosing/blood , T-Lymphocyte Subsets/immunologyABSTRACT
Maternal immune system tolerance to the semiallogeneic fetus is essential for a successful pregnancy; however, the mechanisms underlying this immunotolerance have not been fully elucidated. Here, we demonstrate that myeloid-derived suppressor cells play an important role in maintaining feto-maternal tolerance. A significant expansion of granulocytic myeloid-derived suppressor cells was observed in multiple immune organs and decidual tissues from pregnant mice. Pregnancy-derived granulocytic myeloid-derived suppressor cells suppressed T cell responses in a reactive oxygen species-dependent manner and required direct cell-cell contact. Mechanistic studies showed that progesterone facilitated differentiation and activation of granulocytic myeloid-derived suppressor cells, mediated through STAT3 signaling. The STAT3 inhibitor JSI-124 and a specific short hairpin RNA completely abrogated the effects of progesterone on granulocytic myeloid-derived suppressor cells. More importantly, granulocytic myeloid-derived suppressor cell depletion dramatically enhanced the abortion rate in normal pregnant mice, whereas adoptive transfer of granulocytic myeloid-derived suppressor cells clearly reduced the abortion rate in the CBA/J X DBA/2J mouse model of spontaneous abortion. These observations collectively demonstrate that granulocytic myeloid-derived suppressor cells play an essential role in the maintenance of fetal immunotolerance in mice. Furthermore, our study supports the notion that in addition to their well-recognized roles under pathologic conditions, myeloid-derived suppressor cells perform important functions under certain physiologic circumstances.
Subject(s)
Granulocytes/immunology , Immune Tolerance/immunology , Maternal-Fetal Relations/physiology , Myeloid-Derived Suppressor Cells/immunology , STAT3 Transcription Factor/metabolism , Signal Transduction , T-Lymphocytes/immunology , Abortion, Spontaneous , Adoptive Transfer , Animals , Cell Differentiation , Cells, Cultured , Female , Granulocytes/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Inbred DBA , Myeloid-Derived Suppressor Cells/metabolism , Pregnancy , T-Lymphocytes/metabolismABSTRACT
AIM: To study the effects of dexamethasone on the IL-13-induced mCLCA3 and Muc5ac expressions in nasal mucosa of rats, and the role in mucus secretion of allergic rhinitis. METHODS: Thirty SD rats were randomly divided into control group, IL-13 group and dexamethasone group. Expressions of mCLCA3 mRNA and Muc5ac protein in nasal mucosa were detected by RT-PCR and immunohistochemistry, respectively. RESULTS: No mCLCA3 mRNA expression in the nasal mucosa was detected in the control group, while it was 0.319±0.121 in the IL-13 group (P<0.05 vs control group) and 0.144±0.105 in the dexamethasone group (P<0.05 vs IL-13 group). The expression of Muc5ac protein increased in the IL-13 group (1.389±0.499) as compared with the control group (0.300±0.145, P<0.05). After treatment with dexamethasone, the expression of Muc5ac protein was notably lower (0.901±0.390) than that in IL-13 group (P<0.05). CONCLUSION: IL-13 up-regulates the expressions of mCLCA3 mRNA and Muc5ac protein in nasal mucosa, which may play a pivotal role in the mucus overproduction of nasal mucosa. Dexamethasone substantially down-regulates the expressions of mCLCA3 mRNA and Muc5ac protein, which may have an inhibiting effect on mucus overproduction of nasal mucosa.
