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1.
Am J Pathol ; 180(1): 275-92, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22062220

ABSTRACT

Pulmonary fibrosis is an inflammation-driven lung disease with a poor prognosis and no cure. Here we report that basal toll-like receptor 4 (TLR4) activity is critical for the resolution of acute and chronic inflammation and pulmonary fibrosis in mouse models of lung injury. We found that genetic or pharmacologic inhibition of TLR4 exacerbates bleomycin-induced pulmonary inflammation, fibrosis, dysfunction, and animal death through promoting formation of an immunosuppressive tissue microenvironment and attenuating autophagy-associated degradation of collagen and cell death in the fibrotic lung tissues. In contrast, pharmacologic activation of TLR4 resulted in a quick resolution of acute inflammation, reversed the established pulmonary fibrosis, improved lung function, and rescued mice from death. Similarly, blocking TLR4 impaired the resolution of silica-induced chronic inflammation and fibrosis. Importantly, altering autophagic activity could reverse the TLR4-regulated lung inflammation, fibrosis, dysfunction, and animal death. Rapamycin, an autophagy activator, reversed the effects of TLR4 antagonism. In contrast, inhibition of autophagy by 3-methyladenine reversed the proresolving and antifibrotic roles of TLR4 agonists and increased animal death. These results not only highlight a pivotal role for TLR4-mediated basal immunity, particularly autophagic activity, in the proresolution of inflammation and fibrosis after chemical-induced lung injury but also provide proof for the concept for activating TLR4 signaling, particularly TLR4-mediated autophagy, as a novel therapeutic strategy against chronic fibroproliferative diseases that are unresponsive to current therapy.


Subject(s)
Acute Lung Injury/physiopathology , Idiopathic Pulmonary Fibrosis/physiopathology , Lung Injury/physiopathology , Pneumonia/physiopathology , Toll-Like Receptor 4/physiology , Acute Lung Injury/pathology , Animals , Apoptosis/physiology , Autophagy/physiology , Idiopathic Pulmonary Fibrosis/pathology , Lung Injury/pathology , MAP Kinase Signaling System/physiology , Mice , Pneumonia/pathology , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/deficiency
2.
PLoS One ; 6(9): e24705, 2011.
Article in English | MEDLINE | ID: mdl-21931823

ABSTRACT

BACKGROUND: Immunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown. METHODS AND FINDINGS: Using a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFNγ/STAT1 activation and attenuated tumor metastasis. IFNγ neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFNγ/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis. CONCLUSION AND SIGNIFICANCE: Our studies suggest that activation of IFNγ/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis.


Subject(s)
Immunotherapy/methods , Interferon-gamma/metabolism , STAT1 Transcription Factor/metabolism , Animals , Apoptosis/physiology , Autophagy/physiology , Blotting, Western , Cell Line, Tumor , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Interferon-gamma/genetics , Lung/metabolism , Lung/pathology , Lung/ultrastructure , Melanoma/complications , Melanoma/therapy , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Neoplasm Metastasis/prevention & control , Neoplasm Metastasis/therapy , STAT1 Transcription Factor/genetics , Time Factors
3.
J Immunol ; 187(6): 3003-14, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21841134

ABSTRACT

Pulmonary fibrosis is the pathologic basis for a variety of incurable human chronic lung diseases. IL-17A, a glycoprotein secreted from IL-17-producing cells, has recently been shown to be a proinflammatory cytokine involved in chronic inflammation and autoimmune disease. In this study, we report that IL-17A increased the synthesis and secretion of collagen and promoted the epithelial-mesenchymal transition in alveolar epithelial cells in a TGF-ß1-dependent manner. Using in vivo fibrotic models, we found IL-17A expression to be elevated and IL-17A-associated signaling pathways to be activated in fibrotic lung tissues. Neutralization of IL-17A in vivo promoted the resolution of bleomycin-induced acute inflammation, attenuated pulmonary fibrosis, and increased survival. Additionally, IL-17A antagonism inhibited silica-induced chronic inflammation and pulmonary fibrosis. Targeting IL-17A resulted in a shift of the suppressive immune response in fibrotic lung tissue toward a Th1-type immune response, and it effectively induced autophagy, which promoted the autophagic degradation of collagen and autophagy-associated cell death. Moreover, IL-17A was found to attenuate the starvation-induced autophagy, and autophagy modulators regulated collagen degradation in the alveolar epithelial cells in a TGF-ß1-independent manner. Administration of 3-methylamphetamine, an autophagy inhibitor, reversed the therapeutic efficacy of IL-17A antagonism in pulmonary fibrosis. Our studies indicate that IL-17A participates in the development and progression of pulmonary fibrosis in both TGF-ß1-dependent and -independent manners and that the components of the IL-17A signaling pathway are potential therapeutic targets for the treatment of fibroproliferative lung diseases.


Subject(s)
Interleukin-17/metabolism , Pneumonia/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction/immunology , Transforming Growth Factor beta1/metabolism , Animals , Autophagy , Blotting, Western , Bronchoalveolar Lavage Fluid/chemistry , Cell Separation , Collagen/biosynthesis , Epithelial-Mesenchymal Transition/immunology , Flow Cytometry , Interleukin-17/antagonists & inhibitors , Interleukin-17/immunology , Male , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Pneumonia/immunology , Pneumonia/pathology , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/pathology , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta1/immunology
4.
Acta Pharmacol Sin ; 32(8): 1045-54, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21706041

ABSTRACT

AIM: To explore the pathogenic role of Th17 cells and interleukin-17A (IL-17A)-associated signaling pathways in spontaneous pulmonary emphysema induced by a Toll-like receptor 4 mutant (TLR4(mut)). METHODS: Lungs were obtained from wild-type (WT) or TLR4mut mice that were treated with or without recombinant mouse IL-17A (1 µg·kg(-1)·d(-1), ip) from the age of 3 weeks to 3 months. Pulmonary emphysema was determined using histology, immunochemistry, and biochemical analysis. T cell polarization was determined with flow cytometry, the levels of cytokines were measured using ELISA, and the levels of IL-17A-associated signaling molecules were detected using Western blot. RESULTS: Compared to WT mice, 3 month-old TLR4(mut) mice were characterized by significantly reduced infiltration of Th17 cells into lungs (2.49%±1.13 % νs 5.26%±1.39%), and significantly reduced expression levels of IL-17A (3.66±0.99 pg/µg νs 10.67±1.65 pg/µg), IL-23 (12.43±1.28 pg/µg νs 28.71±2.57 pg/µg) and IL-6 (51.82±5.45 pg/µg νs 92.73±10.91 pg/µg) in bronchoalveolar lavage fluid. In addition, p38 MAPK phosphorylation and AP-1 expression were decreased to 27%±9% and 51%±8%, respectively, of that in WT mice. Treatment of TLR4(mut) mice with IL-17A increased the infiltration of Th17 cells into lungs and expression levels of IL-17A, IL-6, and IL-23 in bronchoalveolar lavage fluid, attenuated MDA and apoptosis, and improved emphysema accompanied with increased phosphorylation of p38 MAPK and expression of AP-1. CONCLUSION: Th17 cells, in particular the cytokine IL-17A, play a crucial role in the pathogenesis of TLR4(mut)-induced spontaneous pulmonary emphysema. Both of them are potential targets for therapeutic strategies for pulmonary emphysema.


Subject(s)
Interleukin-17/metabolism , Pulmonary Emphysema/genetics , Pulmonary Emphysema/metabolism , Th17 Cells/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Animals , Mice , Mice, Inbred C3H , Mutation/genetics
5.
Acta Pharmacol Sin ; 31(12): 1583-92, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21113175

ABSTRACT

AIM: to study whether activation of TLR9 by CpG-ODN would protect against and/or reverse renal fibrosis. METHODS: animals were treated with CpG-ODN before or after undergoing a unilateral ureteral obstruction (UUO) procedure. The interstitial fibrotic lesions of obstructed kidneys were evaluated using histology and immunohistostaining. The Th2-type cytokine profile and the expression and activity of sma and mad related protein (Smad)3, signal transducers and activators of transcription (Stat)3, extracellular regulated protein kinases (ERK), and p38 kinase were determined using RT-PCR or Western blot. RESULTS: the obstructed kidneys displayed a significant increase in interstitial fibrosis, an infiltration of macrophages in the interstitium, and an enhanced expression of Th2 cytokines. Prophylactic application of CpG-ODN (40 microg/kg every 3 days from 2 h before UUO until the 14th day after UUO) suppressed the expression of α-smooth muscle actin, collagen deposition, and hydroxyproline in the UUO kidneys of rats. Moreover, CpG-ODN not only decreased the infiltration of macrophages but also inhibited the expression of chemokines CCL2 and CCL5, the Th2 cytokine IL-13, and the profibrogenic cytokines transforming growth factor (TGF)-ß1 and plasminogen activator inhibitor (PAI)-1 in UUO kidneys of rats. Importantly, therapeutic administration of CpG-ODN (10 microg/mouse, ip, every 3 days from the 4th day to 21st day after UUO) reversed the established renal fibrosis, which was accompanied by significant reductions in the activity of ERK, Smad3, and Stat3 and an increase in the activity of p38 kinase. CONCLUSION: the activation of TLR9 by CpG-ODN attenuates UUO-induced renal fibrosis by reversing an immunosuppressive microenvironment in the fibrotic renal tissue, which might be a novel therapeutic strategy against fibrotic renal diseases.


Subject(s)
Kidney/pathology , Oligodeoxyribonucleotides/therapeutic use , Toll-Like Receptor 9/agonists , Ureteral Obstruction/pathology , Actins/metabolism , Animals , Collagen/metabolism , Fibrosis , Interleukin-13/metabolism , Kidney/metabolism , Kidney Tubules/metabolism , Male , Mice , Mice, Inbred C57BL , Plasminogen Activator Inhibitor 1/metabolism , Rats , Rats, Sprague-Dawley , Transforming Growth Factor beta1/metabolism , Ureteral Obstruction/metabolism
6.
Cardiovasc Res ; 88(1): 140-9, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20542874

ABSTRACT

AIMS: Innate and adaptive immune responses are associated with the development of hypertension-induced myocardial hypertrophy and fibrosis. As a result, we investigated whether heat shock protein (HSP) 70, which is a molecule of damage-associated molecular patterns, could induce inflammation in the myocardium and promote the development of hypertension-induced cardiac hypertrophy and fibrosis. METHODS AND RESULTS: We found that HSP70 serum levels, as well as the amount of HSP70 translocation to the cardiomyocyte membranes and the interstitial space, were elevated in the hypertensive mice caused by abdominal aortic constriction (AAC). Transcriptional inhibition of HSP70 expression by a specific heat shock transcript factor inhibitor, KNK437, reduced the serum level, and the re-distribution of HSP70. It promoted myocardial hypertrophy and cardiac dysfunctions although it protected animals from AAC-induced cardiac fibrosis. On the other hand, the functional antagonism of HSP70 by an anti-HSP70 antibody attenuated AAC-induced cardiac hypertrophy and fibrosis without adverse haemodynamic effects. The cardioprotective effect of the anti-HSP70 antibody was largely attributed to its ability to block AAC-activated immune response in the heart, as was indicated by suppressing the hypertension-enhanced conjugation of HSP70 with toll-like receptor 4, reducing heart-infiltrating macrophages, decreasing the expression of pro-inflammatory factor monocyte chemoattractant protein-1 and profibrotic factor transforming growth factor beta 1, and attenuating pro-hypertrophy signal MAPK P38 and ERK. CONCLUSION: These results indicate that intracellular and extracellular HSP70 have different roles in the regulation of cardiac remodelling and function in response to hypertension. Extracellular HSP70 is a potential therapeutic target against cardiac hypertrophy and fibrosis.


Subject(s)
Blood Pressure , Cardiomegaly/metabolism , HSP70 Heat-Shock Proteins/metabolism , Hypertension/metabolism , Myocardium/metabolism , Ventricular Remodeling , Angiotensin II/metabolism , Animals , Antibodies/administration & dosage , Benzhydryl Compounds/administration & dosage , Cardiomegaly/immunology , Cardiomegaly/physiopathology , Chemokine CCL2/metabolism , Disease Models, Animal , Enzyme Activation , Extracellular Signal-Regulated MAP Kinases/metabolism , Fibrosis , HSP70 Heat-Shock Proteins/antagonists & inhibitors , HSP70 Heat-Shock Proteins/blood , HSP70 Heat-Shock Proteins/genetics , HSP70 Heat-Shock Proteins/immunology , Hypertension/immunology , Hypertension/physiopathology , Male , Mice , Mice, Inbred ICR , Myocardium/immunology , Myocardium/pathology , Protein Transport , Pyrrolidinones/administration & dosage , Signal Transduction , Time Factors , Toll-Like Receptor 4/metabolism , Transcription, Genetic , Transforming Growth Factor beta1/metabolism , Ventricular Remodeling/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism
7.
FEBS Lett ; 584(14): 3028-34, 2010 Jul 16.
Article in English | MEDLINE | ID: mdl-20553715

ABSTRACT

Transforming growth factor-beta1 (TGF-beta1) regulates a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. Here we report that death effector domain-containing DNA-binding protein (DEDD) physically interacts with Smad3. The inhibition of Smad3 by DEDD resulted in a reduction in TGF-beta1/Smad3-mediated transcription. DEDD inhibited the functions of Smad3 by preventing Smad3 phosphorylation, which led to the reduced expression of TGF-beta1/Smad3-targeted genes. TGF-beta1 inhibited DEDD expression, and DEDD inhibited TGF-beta1-mediated invasion. Therefore, our findings suggest that through its interaction with Smad3, DEDD is a novel negative regulator of the TGF-beta1 signaling pathway.


Subject(s)
Signal Transduction/physiology , Transforming Growth Factor beta1/metabolism , Animals , Apoptosis/genetics , Cell Differentiation/genetics , DNA-Binding Proteins , Death Domain Receptor Signaling Adaptor Proteins , Mice , Phosphorylation , Signal Transduction/genetics , Transforming Growth Factor beta1/genetics
8.
Yao Xue Xue Bao ; 45(8): 976-86, 2010 Aug.
Article in English | MEDLINE | ID: mdl-21348427

ABSTRACT

Anti-cancer drug bleomycin (BLM) can cause acute lung injury (ALI) which often results in pulmonary fibrosis due to a failure of resolving acute inflammatory response. The aim of this study is to investigate whether toll-like receptor (TLR) 2 mediates BLM-induced ALI, inflammation and fibrosis. BLM-induced dendritic cells (DCs) maturation was analyzed by flow cytometry and cytokine secretion was detected by the ELISA method. The expression and activity of p38 and ERK MAPK were determined with Western blotting. The roles of TLR2 in ALI, inflammation and fibrosis were investigated in C57BL/6 mice administered intratracheally with BLM. The results demonstrated that BLM-administered mice had higher expression of TLR2 (P<0.001) and its signaling molecules. Blocking TLR2 significantly inhibited the maturation of DCs and reversed BLM-stimulated secretion of cytokines in DCs, such as IL-6 (P<0.001), IL-17 (P<0.05) and IL-23 (P<0.05). TLR2 inhibition attenuated BLM-induced increase of inflammatory cells in bronchoalveolar lavage fluid (BALF), and reversed the immunosuppressive microenvironment by enhancing TH1 response (P<0.05) and inhibiting TH2 (P<0.001), Treg (P<0.01) and TH17 (P<0.01) responses. Importantly, blocking TLR2 in vivo significantly protected BLM-administered mice from pulmonary injury, inflammation and fibrosis and subsequently increased BLM-induced animal survival (from 50% to 92%). Therefore, TLR2 is a novel potential target for ALI and pulmonary fibrosis.


Subject(s)
Acute Lung Injury/metabolism , Cytokines/metabolism , Inflammation/metabolism , Pulmonary Fibrosis/metabolism , Toll-Like Receptor 2/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Bleomycin/toxicity , Bronchoalveolar Lavage Fluid , Cells, Cultured , Dendritic Cells/cytology , Dendritic Cells/metabolism , Inflammation/chemically induced , Inflammation/pathology , Interleukin-17/metabolism , Interleukin-23/metabolism , Interleukin-6/metabolism , Lung/metabolism , MAP Kinase Signaling System , Male , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , T-Lymphocytes, Regulatory/drug effects , Th1 Cells/drug effects , Th2 Cells/drug effects , Toll-Like Receptor 2/physiology
9.
J Dermatolog Treat ; 21(4): 240-4, 2010 Jul.
Article in English | MEDLINE | ID: mdl-19722122

ABSTRACT

OBJECTIVES: The purpose of this study was to observe the improvements of port-wine stains (PWSs) under photodynamic therapy (PDT) and to further evaluate the safety and efficacy of PDT in the dermatology clinic for the treatment of PWSs. METHODS: Total of 75 PWS patients were treated with PDT. The PWS lesions were exposed to the copper vapor laser after intravenous injection of photosensitizer (Photocarcinorin, PsD-007). The lesions were photographed before each session and the therapeutic effects were evaluated by physicians based on the improvements in color, thickness and area of the photographed lesions. A follow-up visit was carried out after 2 months. The improvement rates were classified into 5 grades for quantitation of the therapeutic effects. A decision of termination or continuation of the treatment was then made according to lesion changes. RESULTS: Patients with PWSs responded remarkably to PDT. The complete clinical remission rate was 57.33% and the effective rate was up to 94.67% in no more than four courses of treatment. Among the completely responded patients, 20.93% were treated with no more than two courses. CONCLUSION: PDT is safe and highly effective for the treatment of PWSs in the dermatology clinic.


Subject(s)
Hematoporphyrins/pharmacology , Photochemotherapy/methods , Port-Wine Stain/drug therapy , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Esthetics , Facial Dermatoses/diagnosis , Facial Dermatoses/drug therapy , Female , Follow-Up Studies , Humans , Injections, Intravenous , Male , Patient Satisfaction , Photography , Port-Wine Stain/diagnosis , Retrospective Studies , Severity of Illness Index , Treatment Outcome , Young Adult
10.
Sheng Li Ke Xue Jin Zhan ; 41(1): 5-10, 2010 Feb.
Article in Chinese | MEDLINE | ID: mdl-21417007

ABSTRACT

The interaction of tumor cells with host cells undergoes a progress of immunoediting, including surveillance, equilibrium and escape. The capability of escape from immune-surveillance is a hall marker of tumor cells, which greatly contributes to the tumor growth out of control and the therapy failure in tumor metastasis. It is indicated that tumor cells can recruit amounts of immune cells to tumor site and establish a suppressive immune microenvironment leading to tumor escape. The critical factor for tumor immunotolerance is the establishment of immunosuppressive microenvironment by interaction between pattern recognition receptors with pathogen-associated molecular patterns and damage-associated molecular patterns released from tumor tissue. Therefore, targeting tumor immunotolerance using small molecules or immunostimulatory biological agents such as monoclonal antibody, can inhibit tumor growth and invasion, and subsequently attenuate the tumor metastasis and decrease cancer-caused death.


Subject(s)
Immune Tolerance/immunology , Neoplasms/immunology , Receptors, Pattern Recognition/physiology , Tumor Escape/immunology , Animals , Humans , Neoplasm Metastasis , Neoplasms/pathology
11.
Photomed Laser Surg ; 28(4): 561-3, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20001319

ABSTRACT

OBJECTIVE: To evaluate the safety and efficacy of topical aminolevulinic acid (ALA) photodynamic therapy (PDT) in the treatment of verruca planae. METHODS: A total of 18 patients with facial verruca planae was treated with ALA-PDT. A 10% ALA emulsion was applied on facial lesions for a 4-h incubation period after azone infiltrating for 30 min. Skin lesions of verruca planae were irradiated with 120 J/cm(2) using a 635-nm laser for 10 min. Each patient received at least two sessions at intervals of 15 days. Those with residual lesions after the first session were treated with a third PDT. Before treatment and at each return visit, the lesions were photographed. Patient satisfaction was investigated and therapeutic effect was evaluated at 6 months after termination of the therapy. RESULTS: Fifteen days after the first topical ALA-PDT, 10 patients achieved complete response and 7 patients showed improvement. Complete clinical response was observed in 17 patients after two sessions. At 6 months after termination, only one case relapsed among the complete clinical response patients, and the patient satisfaction rate was 88.89%. CONCLUSION: PDT, utilizing the topical application of 10% ALA, has a good result and excellent cosmetic effects for the treatment of verruca planae.


Subject(s)
Aminolevulinic Acid/administration & dosage , Facial Dermatoses/therapy , Photochemotherapy , Photosensitizing Agents/administration & dosage , Warts/therapy , Administration, Topical , Adolescent , Adult , Female , Humans , Male
12.
Sheng Li Ke Xue Jin Zhan ; 40(3): 234-40, 2009 Jul.
Article in Chinese | MEDLINE | ID: mdl-19803428

ABSTRACT

Molecules of damage-associated molecular patterns (DAMPs) are a class of substances released to intercellular space or peripheral blood by tissues or cells which are stimulated by insults, ischemia or stress. DAMP molecules can be recognized by Toll like receptors, Nod1-like receptors, or Rig-I like receptors and induce autoimmunity or immune tolerance, which play critical roles in various chronic diseases such as arthritis, atherosclerosis, cancer and systemic lupus erythematosus. DAMP molecules include high-mobility group B protein 1, heat shock proteins and S100 proteins etc. The identification of DAMP molecules and clarification of mechanisms of their action will greatly contribute to reveal the pathological mechanisms of chronic diseases and provide a great opportunity to develop the new strategies for the diagnosis, prevention and treatment for these diseases.


Subject(s)
Heat-Shock Proteins , S100 Proteins , Toll-Like Receptors , Animals , Chronic Disease , HMGB1 Protein , Humans , Inflammation
13.
PLoS One ; 4(8): e6520, 2009 Aug 05.
Article in English | MEDLINE | ID: mdl-19654875

ABSTRACT

BACKGROUND: Metastasis is the most pivotal cause of mortality in cancer patients. Immune tolerance plays a crucial role in tumor progression and metastasis. METHODS AND FINDINGS: In this study, we investigated the potential roles and mechanisms of TLR2 signaling on tumor metastasis in a mouse model of intravenously injected B16 melanoma cells. Multiple subtypes of TLRs were expressed on B16 cells and several human cancer cell lines; TLR2 mediated the invasive activity of these cells. High metastatic B16 cells released more heat shock protein 60 than poor metastatic B16-F1 cells. Importantly, heat shock protein 60 released by tumor cells caused a persistent activation of TLR2 and was critical in the constitutive activation of transcription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8(+) T cells and M1 macrophages. Combining an anti-TLR2 antibody and a cytotoxic agent, gemcitabine, provided a further improvement in the survival of tumor-bearing mice. CONCLUSIONS AND SIGNIFICANCE: Our results demonstrate that TLR2 is an attractive target against metastasis and that targeting immunosuppressive microenvironment using anti-TLR2 antibody is a novel therapeutic strategy for combating a life-threatening metastasis.


Subject(s)
Lung Neoplasms/pathology , Melanoma, Experimental/pathology , Neoplasm Metastasis/prevention & control , Toll-Like Receptor 2/antagonists & inhibitors , Animals , Chaperonin 60/metabolism , Chemokines/metabolism , Cytokines/metabolism , Lung Neoplasms/metabolism , Melanoma, Experimental/metabolism , Mice , Toll-Like Receptor 2/immunology , Toll-Like Receptor 2/physiology
14.
J Immunol ; 182(1): 692-702, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-19109203

ABSTRACT

Pulmonary fibrosis is a consequence of chronic lung injury and is associated with a high mortality. Despite the pathogenesis of pulmonary fibrosis remaining as an enigma, immune responses play a critical role in the deregulation of wound healing process after lung injury, which leads to fibrosis. Accumulating evidence argues the rationales for current treatments of pulmonary fibrosis using immunosuppressive agents such as corticosteroids. In this study, we report that bleomycin (BLM), a well-known fibrogenic agent functioning as a TLR2 agonist, induced the maturation of dendritic cells and release of cytokines. The BLM activation of TLR2 mediated a time-dependent alteration of immune responses in the lung. These responses resulted in an increase in the tissue-infiltrating proinflammatory cells and cytokines in the early period initially following BLM exposure and an increase in the tissue-infiltrating suppressive immune cells and factors during the later period following BLM exposure. TLR2 deficiency, however, reduced pulmonary inflammation, injury, and subsequently attenuated pulmonary fibrosis. Targeting TLR2 by a TLR2-neutralizing Ab not only markedly decreased animal death but also protected animals from the development of pulmonary fibrosis and reversed the established pulmonary fibrosis through regulating BLM-induced immunosuppressive microenvironments. Our studies suggest that TLR2 is a promising target for the development of therapeutic agents against pulmonary fibrosis and that eliminating immunosuppressive cells and factors via immunostimulants is a novel strategy for fibro-proliferative diseases. Moreover, combining BLM with an anti-TLR2 Ab or TLR2 antagonist for cancer therapy will improve the BLM therapeutic profile by enhancing anti-cancer efficacy and reducing systemic inflammation and pulmonary fibrosis.


Subject(s)
Bleomycin/toxicity , Immunosuppressive Agents , Inflammation Mediators/antagonists & inhibitors , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/prevention & control , Toll-Like Receptor 2/antagonists & inhibitors , Toll-Like Receptor 2/deficiency , Animals , Bleomycin/adverse effects , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cell Movement/drug effects , Cell Movement/immunology , Cells, Cultured , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/pathology , Disease Models, Animal , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/toxicity , Inflammation Mediators/metabolism , Inflammation Mediators/physiology , Intubation, Intratracheal , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/metabolism , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/pathology , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/physiology
15.
Sheng Li Ke Xue Jin Zhan ; 40(4): 297-302, 2009 Oct.
Article in Chinese | MEDLINE | ID: mdl-21417026

ABSTRACT

B cells are typically characterized by their ability to regulate the immune responses through presenting antigens and producing antibodies. However, a novel B cell subset, named regulatory B cells (Bregs), has been identified. As Tregs, the Bregs are capable of performing both pathogenic and regulatory functions by production of suppressive cytokines, such as IL-10 or TGF-beta1, or by interaction with pathogen T cells or other immune cells. Recent studies indicate that the Bregs play a critical role in the development and resolution of multiple chronic diseases, including inflammatory bowel disease, rheumatoid arthritis, and experimental autoimmune encephalomyelitis. The identification and the clarification of action mechanisms of the Bregs will greatly contribute to understanding the mechanisms of immune tolerance comprehensively and deeply, and to develop the rational therapeutic strategies for arthritis, diabetes, multiple sclerosis, infectious diseases and cancer, etc. In this review, we summarized the recent insights of identification, characterizations, development, and regulation mechanisms of Bregs and these cells' contribution to the pathogenesis of inflammatory diseases.


Subject(s)
B-Lymphocytes, Regulatory/immunology , Immune Tolerance , Animals , Humans , Inflammation
16.
Sheng Li Ke Xue Jin Zhan ; 39(2): 114-8, 2008 Apr.
Article in Chinese | MEDLINE | ID: mdl-18664173

ABSTRACT

Toll-like receptors (TLRs) are widely expressed in the innate and adaptive immune system. They initiate host defense against endogenous and exogenous pathogens containing conserved pathogen associated molecular patterns. TLRs are critical bridges between the innate and adaptive immunity, especially the cellular immunity mediated by T cells. Emerging evidence indicated that B cells express almost all subtypes of TLRs. TLRs play critical role not only in regulation of proliferation, maturation and function of B cells, but also in pathogenesis of diseases, such as systemic lupus erythematosus and chronic lymphocytic leukemia. Targeting TLRs of B cells is a promising therapeutic strategy for these disorders.


Subject(s)
B-Lymphocytes/metabolism , Toll-Like Receptors/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/physiology , Humans , Signal Transduction , Toll-Like Receptors/immunology , Toll-Like Receptors/physiology
17.
J Immunol ; 180(11): 7349-57, 2008 Jun 01.
Article in English | MEDLINE | ID: mdl-18490734

ABSTRACT

Hypertension-induced cardiovascular hypertrophy and fibrosis are critical in the development of heart failure. The activity of TLRs has been found to be involved in the development of pressure overload-induced myocardial hypertrophy and cardiac fibrosis. We wondered whether vaccine bacillus Calmette-Guérin (BCG), which activated TLR4 to elicit immune responses, modulated the pressure overload-stimulated cardiovascular hypertrophy and cardiac fibrosis in the murine models of abdominal aortic constriction (AAC)-induced hypertension. Before or after AAC, animals received BCG, TLR4 agonist, IFN-gamma, or TLR4 antagonist i.p. BCG and TLR4 agonist significantly prevented AAC-induced cardiovascular hypertrophy and reactive cardiac fibrosis with no changes in hemodynamics. Moreover, TLR4 antagonist reversed the BCG- and TLR4 agonist-induced actions of anti-cardiovascular hypertrophy and cardiac fibrosis. BCG decreased the expression of TLR2 or TLR4 on the heart tissue but TLR4 agonist increased the expression of TLR2 or TLR4 on the immune cells that infiltrate into the heart tissue. This led to an increased expression ratio of IFN-gamma/TGF-beta in the heart. The cardiac protective effects of BCG and TLR4 agonist are related to their regulation of ERK-Akt and p38-NF-kappaB signal pathways in the heart. In conclusion, the activity of TLR4 plays a critical role in the mediation of pressure overload-induced myocardial hypertrophy and fibrosis. The regulation of immune responses by BCG and TLR4 agonist has a great potential for the prevention and treatment of hypertension-induced myocardial hypertrophy and cardiac fibrosis.


Subject(s)
BCG Vaccine/immunology , Cardiomegaly/immunology , Interferon-gamma/metabolism , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism , Acyltransferases/pharmacology , Animals , BCG Vaccine/administration & dosage , Cardiomegaly/prevention & control , Cardiovascular System/immunology , Dendritic Cells/cytology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Disease Models, Animal , Escherichia coli Proteins/pharmacology , Fibrosis/immunology , Fibrosis/prevention & control , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Interferon-gamma/immunology , Lipopolysaccharides/immunology , Male , Mice , Mice, Inbred Strains , Mitogen-Activated Protein Kinase Kinases/metabolism , Myocardium/pathology , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Toll-Like Receptor 2/immunology , Toll-Like Receptor 4/agonists , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/immunology , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/metabolism
18.
Yao Xue Xue Bao ; 43(2): 113-7, 2008 Feb.
Article in Chinese | MEDLINE | ID: mdl-18507334

ABSTRACT

Altered peptide ligand (APL), a short peptide with immune regulatory activity and substitutions of a single or multiple amino acids in an antigenic peptide, has shown potential therapeutic effect on autoimmune disease, tumor and virus infection. APL regulates immune responses by interfering the interaction between the major histocompatibility complex (MHC), antigenic peptide and T cell receptor (TCR), or by regulating the intracellular signaling of antigen presenting cells, bystander suppression and inducing heterogenous immune responses. High-specific and high-affinity APL screened from peptide laboratory by phage display, has a potential to be a new resource for drug with antigen specificity.


Subject(s)
Autoimmune Diseases/therapy , Peptide Fragments , Peptide Library , Receptors, Antigen, T-Cell/immunology , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Autoimmune Diseases/immunology , Humans , Immunotherapy/methods , Ligands , Major Histocompatibility Complex/immunology , Peptide Fragments/biosynthesis , Peptide Fragments/immunology , Peptide Fragments/metabolism , Peptide Fragments/therapeutic use , Receptors, Antigen, T-Cell/metabolism
19.
J Med Chem ; 48(16): 5112-22, 2005 Aug 11.
Article in English | MEDLINE | ID: mdl-16078831

ABSTRACT

N(2)-[alpha-O-benzyl-N-(acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N(6)-trans-(m-nitrocinnamoyl)-L-lysine (muramyl dipeptide C, or MDP-C) has been synthesized as a novel, nonspecific immunomodulator. The present study shows that MDP-C induces strong cytolytic activity by macrophages on P388 leukemia cells and cytotoxic activity by cytotoxic T lymphocytes (CTLs) on P815 mastocytoma cells. Our results also indicate that MDP-C is an effective stimulator for production of interleukin-2 and interleukin-12 by murine bone marrow derived dendritic cells (BMDCs) and production of interferon-gamma by CTLs. Additionally, MDP-C increases the expression levels of several surface molecules, including CD11c, MHC class I, and intercellular adhesion molecule-1 in BMDCs. Moreover, MDP-C remarkably enhances the immune system's responsiveness to hepatitis B surface antigen (HBsAg) in hepatitis B virus transgenic mice for both antibody production and specific HBsAg T-cell responses ex vivo. Our results indicate that MDP-C is an apyrogenic, nonallergenic, and low-toxicity immunostimulator with great potential for diagnostic, immunotherapeutic, and prophylactic applications in diseases such as hepatitis B and cancers.


Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Adjuvants, Immunologic/chemical synthesis , Hepatitis B Surface Antigens/immunology , Acetylmuramyl-Alanyl-Isoglutamine/adverse effects , Acetylmuramyl-Alanyl-Isoglutamine/chemical synthesis , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Adjuvants, Immunologic/adverse effects , Adjuvants, Immunologic/pharmacology , Animals , Antibody Formation , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , CD11c Antigen/biosynthesis , Cell Line, Tumor , Cytotoxicity, Immunologic , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Hepatitis B/immunology , Hepatitis B Vaccines/immunology , Histocompatibility Antigens Class I/biosynthesis , In Vitro Techniques , Intercellular Adhesion Molecule-1/biosynthesis , Interleukin-12/biosynthesis , Interleukin-2/biosynthesis , Macrophages/drug effects , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Rabbits , Rats , Rats, Wistar , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , Toxicity Tests, Acute
20.
Yao Xue Xue Bao ; 40(4): 332-6, 2005 Apr.
Article in English | MEDLINE | ID: mdl-16011261

ABSTRACT

AIM: To study the effects of ginsenoside-Ro on cell proliferation and cytokine production in murine splenocytes. METHODS: The effect of ginsenoside-Ro on murine splenocytes proliferation was studied using [3H] thymidine incorporation assay. Effects of ginsenoside-Ro on the production of cytokines interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) from murine splenocytes were detected by ELISA method. Effects of ginsenoside-Ro on mRNA level of Th1 cytokine IFN-gamma and Th2 cytokine IL-4 were evaluated by reverse transcription polymerase chain reaction (RT-PCR) analysis. RESULTS: Ginsenoside-Ro showed no mitogenic effect on unstimulated murine splenocytes. It enhanced the proliferation of Con A-induced murine splenocytes and the production of IL-2 at concentrations of 1-10 micromol x L(-1). Moreover, ginsenoside-Ro increased the production and expression of Th2 cytokine IL-4 and decreased the production and expression of Th1 cytokine IFN-gamma in Con A-induced murine splenocytes at concentrations of 2-10 micromol x L(-1). CONCLUSION: Ginsenoside-Ro showed immunomodulatory effects by regulating the production and expression of Th1/Th2 cytokines in murine splenocytes.


Subject(s)
Cell Proliferation/drug effects , Ginsenosides/pharmacology , Interferon-gamma/biosynthesis , Interleukin-4/biosynthesis , Spleen/metabolism , Animals , Ginsenosides/isolation & purification , Interferon-gamma/genetics , Interleukin-2/metabolism , Interleukin-4/genetics , Male , Mice , Mice, Inbred BALB C , Panax/chemistry , Plants, Medicinal/chemistry , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Spleen/cytology
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