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GPBAR1/TGR5 Mediates Bile Acid-Induced Cytokine Expression in Murine Kupffer Cells  [PDF]
Guiyu Lou, Xiaoxiao Ma, Xianghui Fu, Zhipeng Meng, Wenyu Zhang, Yan-Dong Wang, Carl Van Ness, Donna Yu, Rongzhen Xu, Wendong Huang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093567
Abstract: GPBAR1/TGR5 is a novel plasma membrane-bound G protein–coupled bile acid (BA) receptor. BAs are known to induce the expression of inflammatory cytokines in the liver with unknown mechanism. Here we show that without other external stimuli, TGR5 activation alone induced the expression of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) in murine macrophage cell line RAW264.7 or murine Kupffer cells. The TGR5-mediated increase of pro-inflammatory cytokine expression was suppressed by JNK inhibition. Moreover, the induced pro-inflammatory cytokine expression in mouse liver by 1% cholic acid (CA) diet was blunted in JNK?/? mice. TGR5 activation by its ligands enhanced the phosphorylation levels, DNA-binding and trans-activities of c-Jun and ATF2 transcription factors. Finally, the induced pro-inflammatory cytokine expression in Kupffer cells by TGR5 activation correlated with the suppression of Cholesterol 7α-hydroxylase (Cyp7a1) expression in murine hepatocytes. These results suggest that TGR5 mediates the BA-induced pro-inflammatory cytokine production in murine Kupffer cells through JNK-dependent pathway. This novel role of TGR5 may correlate to the suppression of Cyp7a1 expression in hepatocytes and contribute to the delicate BA feedback regulation.
Interleukin-2 mediates the peripheral analgesia of interferon alpha
Li Li,Qiwei Zhai,Wei Tang,Tong Wu,Zhongcheng Zheng,Xinyuan Liu
Chinese Science Bulletin , 1999, DOI: 10.1007/BF02896284
Abstract: Interferonα (IFNα) and interleukin-2 (IL-2) are crucial cytokines in immune system. They also play an important role in nerve system. It has been reported that IL-2 can induce the central analgesia. It is demonstrated that IFNα also can induce the peripheral analgesia, which can be blocked by naloxone as IL-2. Furthermore, the analgesic effect of IFN-α is reversible by monoclonal anti-IL-2 antibody.In vitro experiments show that IFN-α significantly increases the production of IL-2 in a dose dependent manner. These data suggest that IL-2 mediates the peripheral analgesia of IFN-α.
Interleukin-2 mediates the peripheral analgesia of interferon alpha

Li Li,Qiwei Zhai,Wei Tang,Tong Wu,Zhongcheng Zheng,Xinyuan Liu,

科学通报(英文版) , 1999,
Abstract: Interferonα (IFNα) and interleukin-2 (IL-2) are crucial cytokines in immune system. They also play an important role in nerve system. It has been reported that IL-2 can induce the central analgesia. It is demonstrated that IFNα also can induce the peripheral analgesia, which can be blocked by naloxone as IL-2. Furthermore, the analgesic effect of IFN-α is reversible by monoclonal anti-IL-2 antibody.In vitro experiments show that IFN-α significantly increases the production of IL-2 in a dose dependent manner. These data suggest that IL-2 mediates the peripheral analgesia of IFN-α.
Interleukin-17A Mediates Acquired Immunity to Pneumococcal Colonization  [PDF]
Ying-Jie Lu equal contributor,Jane Gross equal contributor,Debby Bogaert equal contributor,Adam Finn,Linda Bagrade,Qibo Zhang,Jay K. Kolls,Amit Srivastava,Anna Lundgren,Sophie Forte,Claudette M. Thompson,Kathleen F. Harney,Porter W. Anderson,Marc Lipsitch ?,Richard Malley ?
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000159
Abstract: Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell–dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to na?ve RAG1?/? mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-γ or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines.
Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes  [PDF]
Elena Vecile, Aldo Dobrina, Fadi N. Salloum, Benjamin W. Van Tassell, Antonella Falcione, Edoardo Gustini, Samuele Secchiero, Sergio Crovella, Gianfranco Sinagra, Nicoletta Finato, Martin J. Nicklin, Antonio Abbate
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053265
Abstract: Background Loss of cardiac myocytes due to apoptosis is a relevant feature of ischemic heart disease. It has been described in infarct and peri-infarct regions of the myocardium in coronary syndromes and in ischemia-linked heart remodeling. Previous studies have provided protection against ischemia-induced cardiomyocyte apoptosis by the anti-inflammatory cytokine interleukin-1 receptor-antagonist (IL-1Ra). Mitochondria triggering of caspases plays a central role in ischemia-induced apoptosis. We examined the production of IL-1Ra in the ischemic heart and, based on dual intra/extracellular function of some other interleukins, we hypothesized that IL-1Ra may also directly inhibit mitochondria-activated caspases and cardiomyocyte apoptosis. Methodology/Principal Findings Synthesis of IL-1Ra was evidenced in the hearts explanted from patients with ischemic heart disease. In the mouse ischemic heart and in a mouse cardiomyocyte cell line exposed to long-lasting hypoxia, IL-1Ra bound and inhibited mitochondria-activated caspases, whereas inhibition of caspase activation was not observed in the heart of mice lacking IL-1Ra (Il-1ra?/?) or in siRNA to IL-1Ra-interfered cells. An impressive 6-fold increase of hypoxia-induced apoptosis was observed in cells lacking IL-1Ra. IL-1Ra down-regulated cells were not protected against caspase activation and apoptosis by knocking down of the IL-1 receptor, confirming the intracellular, receptor-independent, anti-apoptotic function of IL-1Ra. Notably, the inhibitory effect of IL-1Ra was not influenced by enduring ischemic conditions in which previously described physiologic inhibitors of apoptosis are neutralized. Conclusions/Significance These observations point to intracellular IL-1Ra as a critical mechanism of the cell self-protection against ischemia-induced apoptosis and suggest that this cytokine plays an important role in the remodeling of heart by promoting survival of cardiomyocytes in the ischemic regions.
Cholestasis in a murine experimental model: lesions include hepatocyte ischemic necrosis
Prado, Ivete Bedin;Santos, Marília Harumi Higuchi dos;Lopasso, Fábio Pinatel;Iriya, Kiyoshi;Laudanna, Antonio Atílio;
Revista do Hospital das Clínicas , 2003, DOI: 10.1590/S0041-87812003000100006
Abstract: objective: to establish a murine experimental model of bile duct obstruction that would enable controlled observations of the acute and subacute phases of cholestasis. methodology: adult male isogenic balb/c mice underwent a bile duct ligation (22 animals) or a sham operation (10 animals). fifteen days after surgery, or immediately after the animal's death, macroscopic findings were noted and histological study of the liver, biliary tree, and pancreas was performed (hematoxylin-eosin and masson trichromic staining). results: beginning 24 hours after surgery, all animals from the bile duct ligation group presented progressive generalized malaise. all animals presented jaundice in the parietal and visceral peritoneum, turgid and enlarged liver, and accentuated dilatation of gallbladder and common bile duct. microscopic findings included marked dilatation and proliferation of bile ducts with accentuated collagen deposits, frequent areas of ischemic necrosis, hepatic microabscesses, and purulent cholangitis. animals from the sham operation group presented no alterations. conclusion: we established a murine experimental model of induced cholestasis, which made it possible to study acute and subacute tissue lesions. our data suggests that in cholestasis, hepatic functional ischemia plays an important role in inducing hepatic lesions, and it also suggests that the infectious process is an important factor in morbidity and mortality.
Cholestasis in a murine experimental model: lesions include hepatocyte ischemic necrosis  [cached]
Prado Ivete Bedin,Santos Marília Harumi Higuchi dos,Lopasso Fábio Pinatel,Iriya Kiyoshi
Revista do Hospital das Clínicas , 2003,
Abstract: OBJECTIVE: To establish a murine experimental model of bile duct obstruction that would enable controlled observations of the acute and subacute phases of cholestasis. METHODOLOGY: Adult male isogenic BALB/c mice underwent a bile duct ligation (22 animals) or a sham operation (10 animals). Fifteen days after surgery, or immediately after the animal's death, macroscopic findings were noted and histological study of the liver, biliary tree, and pancreas was performed (hematoxylin-eosin and Masson trichromic staining). RESULTS: Beginning 24 hours after surgery, all animals from the bile duct ligation group presented progressive generalized malaise. All animals presented jaundice in the parietal and visceral peritoneum, turgid and enlarged liver, and accentuated dilatation of gallbladder and common bile duct. Microscopic findings included marked dilatation and proliferation of bile ducts with accentuated collagen deposits, frequent areas of ischemic necrosis, hepatic microabscesses, and purulent cholangitis. Animals from the sham operation group presented no alterations. CONCLUSION: We established a murine experimental model of induced cholestasis, which made it possible to study acute and subacute tissue lesions. Our data suggests that in cholestasis, hepatic functional ischemia plays an important role in inducing hepatic lesions, and it also suggests that the infectious process is an important factor in morbidity and mortality.
Interleukin-6 Mediates Epithelial–Stromal Interactions and Promotes Gastric Tumorigenesis  [PDF]
Hiroto Kinoshita, Yoshihiro Hirata, Hayato Nakagawa, Kei Sakamoto, Yoku Hayakawa, Ryota Takahashi, Wachiko Nakata, Kosuke Sakitani, Takako Serizawa, Yohko Hikiba, Masao Akanuma, Wataru Shibata, Shin Maeda, Kazuhiko Koike
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060914
Abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial–stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6–positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6?/?) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6?/? mice, compared with WT mice. Impaired tumor development in IL-6?/? mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3–related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell–conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.
Parathyroid Hormone Mediates Hematopoietic Cell Expansion through Interleukin-6  [PDF]
Flavia Q. Pirih,Megan N. Michalski,Sun W. Cho,Amy J. Koh,Janice E. Berry,Eduardo Ghaname,Pachiyappan Kamarajan,Edith Bonnelye,Charles W. Ross,Yvonne L. Kapila,Pierre Jurdic,Laurie K. McCauley
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013657
Abstract: Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control. Flt-3L alone increased adherent and non-adherent cells. PTH did not directly impact hematopoietic or osteoclastic cells but acted in concert with Flt-3L to further increase cell numbers. Flt-3L alone stimulated proliferation, while PTH combined with Flt-3L decreased apoptosis. Flt-3L increased blasts early in culture, and later increased CD45+ and CD11b+ cells. In parallel experiments, IL-6 acted additively with Flt-3L to increase cell numbers and IL-6-deficient bone marrow cultures (compared to wildtype controls) but failed to amplify in response to Flt-3L and PTH, suggesting that IL-6 mediated the PTH effect. In vivo, PTH increased Lin- Sca-1+c-Kit+ (LSK) hematopoietic progenitor cells after PTH treatment in wildtype mice, but failed to increase LSKs in IL-6-deficient mice. In conclusion, PTH acts with Flt-3L to maintain hematopoietic cells by limiting apoptosis. IL-6 is a critical mediator of bone marrow cell expansion and is responsible for PTH actions in hematopoietic cell expansion.
Interleukin-6 Mediates Angiotensinogen Gene Expression during Liver Regeneration  [PDF]
Hong-Shiee Lai, Wen-Hsi Lin, Shuo-Lun Lai, Hao-Yu Lin, Wen-Ming Hsu, Chia-Hung Chou, Po-Huang Lee
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067868
Abstract: Background Angiotensinogen is the precursor of angiotensin II, which is associated with ischemia-reperfusion injury. Angiotensin II reduces liver regeneration after hepatectomy and causes dysfunction and failure of reduced-size liver transplants. However, the regulation of angiotensinogen during liver regeneration is still unclear. Aims To investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration. Methods A mouse in vitro partial hepatectomy animal model was used to evaluate the expression of interleukin-6 (IL-6) and angiotensinogen during liver regeneration. Serum IL-6 and angiotensinogen were detected by enzyme immunoassay (EIA). Angiotensinogen mRNA was detected by RT-PCR. Tissue levels of angiotensinogen protein were detected by Western blot analysis. Primary cultures of mouse hepatocytes were used to investigate IL-6-induced angiotensinogen. Chemical inhibitors were used to perturb signal transduction pathways. Synthetic double-stranded oligodeoxynucleotides (ODNs) were used as ‘decoy’ cis-elements to investigate transcription. Ki 67 staining and quantification were used to verify liver regeneration. Results In the in vivo model, the levels of serum IL-6 and angiotensinogen correlated. In the in vitro model, IL-6 transcriptionally regulated angiotensinogen expression. Additionally, IL-6 mediated angiotensinogen expression through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and JAK/p38 signaling. Decoy ODN analyses revealed that STAT3 and nuclear factor-kB (NF-kB) also played critical roles in the transcriptional regulation of angiotensinogen by IL-6. IL-6-mediated signaling, JAK2, STAT3 and p38 inhibitors reduced angiotensinogen expression in the partially hepatectomized mice. Conclusion During liver regeneration, IL-6-enhanced angiotensinogen expression is dependent on the JAK/STAT3 and JAK/p38/NF-kB signaling pathways. Interruption of the molecular mechanisms of angiotensinogen regulation may be applied as the basis of therapeutic strategies for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.
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