scholarly journals AB0098 THE EFFECT OF MALT1-DEFICIENCY ON THE EFFECTOR PHASE OF EXPERIMENTAL AUTOIMMUNE ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1348.1-1349
Author(s):  
T. Nemeth ◽  
K. Futosi ◽  
J. Ruland ◽  
A. Mocsai
Keyword(s):  
Clinical Signs ◽  
Joint Inflammation ◽  
Wild Type ◽  
Potential Therapeutic Target ◽  
Single Intraperitoneal Injection ◽  
Effector Phase ◽  
Serum Transfer ◽  
Experimental Process ◽  
Experimental Autoimmune

Background:The paracaspase Malt1 is a cysteine protease, which forms a complex leading to the activation of the in proinflammatory transcription factor NF-κB in lymphocytes with CARMA1 and Bcl10. Previously, we showed that the myeloid equivalent of CARMA1, Card9 is important in neutrophils in Fcγ receptor-mediated cytokine release together with Bcl10 and Malt1. In line with these findings, we observed a significant decrease in the severity of autoantibody-triggered arthritis in the absence of Card9 and Bcl10.Objectives:Our aim was to directly investigate whether the genetic deficiency of Malt1, the third component of the complex altered the process of the K/BxN serum transfer arthritis (that resembles to the effector phase of rheumatoid arthritis).Methods:We used wild type and Malt1–/–mice for our experiments. Autoantibody-mediated arthritis was induced by a single intraperitoneal injection of K/BxN serum. Clinical signs of joint inflammation were scored on a scale based on the cardinal inflammatory clues for two weeks. Ankle thickness was measured by a spring-loaded caliper.Results:Similar to the deficiency of the other two components of the complex, Malt1–/–mice showed a partial, but significant decrease in the macroscopic joint inflammation compared to arthritic serum-treated wild type animals during the entire experimental process. In line with this phenomenon, Malt1–/–animals had reduced autoantibody-triggered ankle thickening.Conclusion:Our results show that Malt1 seems to be an important molecule in the development and progression of experimental autoantibody-induced arthritis in mice, highlighting the role of the molecule as a potential therapeutic target in the future.Disclosure of Interests:None declared

scholarly journals Studies in B7-Deficient Mice Reveal a Critical Role for B7 Costimulation in Both Induction and Effector Phases of Experimental Autoimmune Encephalomyelitis

1999 ◽  
Vol 190 (5) ◽  
pp. 733-740 ◽  
Author(s):  
Tammy T. Chang ◽  
Claudia Jabs ◽  
Raymond A. Sobel ◽  
Vijay K. Kuchroo ◽  
Arlene H. Sharpe
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Autoreactive T Cells ◽  
Effector Phase ◽  
Deficient Mice ◽  
Experimental Autoimmune

The importance of B7 costimulation in regulating T cell expansion and peripheral tolerance suggests that it may also play a significant regulatory role in the development of autoimmune disease. It is unclear whether B7 costimulation is involved only in the expansion of autoreactive T cells in the periphery, or if it is also required for effector activation of autoreactive T cells in the target organ for mediating tissue injury and propagating autoimmune disease. In this study, the role of B7–CD28 costimulation and the relative importance of B7 costimulators for the induction and effector phases of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) peptide were examined. Wild-type, B7-1/B7-2–deficient mice, or CD28-deficient C57BL/6 mice were immunized with MOG 35-55 peptide. Mice lacking both B7-1 and B7-2 or CD28 showed no or minimal clinical signs of EAE and markedly reduced inflammatory infiltrates in the brain and spinal cord. However, mice lacking either B7-1 or B7-2 alone developed clinical and pathologic EAE that was comparable to EAE in wild-type mice, indicating overlapping functions for B7-1 and B7-2. Resistance to EAE was not due to a lack of induction of T helper type 1 (Th1) cytokines, since T cells from B7-1/B7-2−/− mice show reduced proliferative responses, but greater interferon γ production compared with T cells from wild-type mice. To study the role of B7 molecules in the effector phase of the disease, MOG 35-55–specific T lines were adoptively transferred into the B7-1/B7-2−/− and wild-type mice. Clinical and histologic EAE were markedly reduced in B7-1/B7-2−/− compared with wild-type recipient mice. These results demonstrate that B7 costimulation has critical roles not only in the initial activation and expansion of MOG-reactive T cells, but also in the effector phase of encephalitogenic T cell activation within the central nervous system.

scholarly journals Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis

2006 ◽  
Vol 203 (2) ◽  
pp. 325-335 ◽  
Author(s):  
Tetsuya Honda ◽  
Eri Segi-Nishida ◽  
Yoshiki Miyachi ◽  
Shuh Narumiya
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
The Other ◽  
Receptor Subtype ◽  
Significant Suppression ◽  
Wild Type ◽  
Collagen Induced Arthritis

Prostaglandin (PG)I2 (prostacyclin [PGI]) and PGE2 are abundantly present in the synovial fluid of rheumatoid arthritis (RA) patients. Although the role of PGE2 in RA has been well studied, how much PGI2 contributes to RA is little known. To examine this issue, we backcrossed mice lacking the PGI receptor (IP) to the DBA/1J strain and subjected them to collagen-induced arthritis (CIA). IP-deficient (IP−/−) mice exhibited significant reduction in arthritic scores compared with wild-type (WT) mice, despite anti-collagen antibody production and complement activation similar to WT mice. IP−/− mice also showed significant reduction in contents of proinflammatory cytokines, such as interleukin (IL)-6 in arthritic paws. Consistently, the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced IL-6 production and induced expression of other arthritis-related genes. On the other hand, loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA. However, a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4. Our results show significant roles of both PGI2-IP and PGE2-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE2 synthesis alone may not be sufficient for suppression of RA symptoms.

scholarly journals Experimental infection of rabbits with a recombinant bovine herpesvirus type 5 (BoHV-5) gI, gE and US9-negative

2009 ◽  
Vol 29 (11) ◽  
pp. 913-918 ◽  
Author(s):  
Alessandra D'Avila Silva ◽  
Ana Cláudia Franco ◽  
Paulo Augusto Esteves ◽  
Fernando Rosado Spilki ◽  
Paulo Michel Roehe
Keyword(s):  
Neurological Disease ◽  
Age Groups ◽  
Clinical Signs ◽  
Bovine Herpesvirus ◽  
Wild Type ◽  
Herpesvirus Type ◽  
Viral Genes ◽  
Bovine Herpesvirus Type 5 ◽  
Two Age Groups

Bovine herpesvirus type 5 (BoHV-5) is a major cause of viral meningoencephalitis in cattle. The expression of different viral proteins has been associated with BoHV-5 neuropathogenesis. Among these, gI, gE and US9 have been considered essential for the production of neurological disease in infected animals. To evaluate the role of gI, gE and US9 in neurovirulence, a recombinant from which the respective genes were deleted (BoHV-5 gI-/gE-/US9-) was constructed and inoculated in rabbits of two age groups (four and eight weeks-old). When the recombinant virus was inoculated through the paranasal sinuses of four weeks-old rabbits, neurological disease was observed and death was the outcome in 4 out of 13 (30.7 %) animals, whereas clinical signs and death were observed in 11/13 (84.6%) of rabbits infected with the parental virus. In eight weeks-old rabbits, the BoHV-5 gI-/gE-/US9- did not induce clinically apparent disease and could not be reactivated after dexamethasone administration, whereas wild type BoHV-5 caused disease in 55.5% of the animals and was reactivated. These findings reveal that the simultaneous deletion of gI, gE and US9 genes did reduce but did not completely abolish the neurovirulence of BoHV-5 in rabbits, indicating that other viral genes may also play a role in the induction of neurological disease.

TNF-alpha protects from exacerbated autoinflammatory response in mouse model of experimental autoimmune myocarditis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Rolski ◽  
K Weglarczyk ◽  
P Pelczar ◽  
M Siedlar ◽  
B Ludewig ◽  
...  
Keyword(s):  
T Cells ◽  
High Dose ◽  
Wild Type ◽  
Autoimmune Myocarditis ◽  
Heart Failure Patients ◽  
Tnf Α ◽  
Intercellular Adhesion Molecules ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Abstract Background Myocarditis is an inflammatory heart disease and heart-specific autoimmunity plays an important role in development and progression of the disease. TNF-α is a potent pro-inflammatory cytokine implicated in pathogenesis in many inflammatory diseases. Unexpectedly, clinical studies showed that high dose anti-TNF-α therapy increased hospitalization and mortality of heart failure patients. Purpose To elucidate the role of TNF-α in heart-specific autoimmunity and in activation of cardiac microvascular endothelial cells in autoimmune response. Methods Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice by immunization with α-myosin heavy chain peptide (α-MyHC) together with complete Freund's adjuvant. Development of myocarditis in the absence of adjuvant was analysed in TCR-M mice, which CD4+ T cells expressed transgenic T cell receptor recognizing α-MyHC. The role of TNF-α was addressed using haploinsufficient Tnf+/−, knockout Tnf−/− and TCR-M x Tnf+/− mice. Effects of antigen-dependent T cell response on cardiac microvascular endothelial cell (cMVEC) activation were assessed by flow cytometry, immunoblotting and leukocyte-endothelium adhesion assay. Inflammatory cells were phenotyped using flow cytometry, cytokine production was measured by ELISA. Results EAM induction resulted in reduced prevalence of myocarditis in Tnf+/− and Tnf−/− comparing wild-type mice at day 21 after disease induction. However, Tnf+/− and Tnf−/− mice that developed myocarditis showed higher severity of the disease than wild-type controls. On the other hand, TCR-M x Tnf+/− mice showed exacerbated myocarditis at age of 2 months and were characterized by increased mortality comparing with TCR-M controls. TCR-M Tnf+/− mice showed increased total number of cardiac infiltrates compared to TCR-M controls, but no difference in myeloid subsets were observed. In contrast, Tnf+/− and Tnf−/− mice showed significantly increased percentage of T effector cells in spleens and blood in both myocarditis models. Stimulation with rTNF-α induced expression of intercellular adhesion molecules (ICAM1, VCAM1 and P-selectin) on cMVECs, which was associated with increased ability to bind leukocytes under shear flow conditions. TNF-α deficiency had, however, no impact on antigen-specific activation and proliferation of T-cells. Medium conditioned of antigen-activated wild-type, Tnf+/− and Tnf−/− CD4+ T cells showed similar cMVEC activation measured by increased expression of intercellular adhesion molecules and binding of leukocytes under shear flow condition. Furthermore, Tnf+/− and Tnf−/m- myeloid cells showed increased production of IL-6. Conclusions Our data suggest that TNF-α protects the heart from excessive autoimmune reaction by suppressing expansion of autoreactive effector T cells. Thus, this study uncovers a cardioprotective role of proinflammatory TNF-α and potentially can explain the deleterious effect of high dose anti-TNF-α therapy in heart failure patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Science Centre Poland

scholarly journals Inhibiting MAPK14 showed anti-prolactinomas effect

2020 ◽  
Author(s):  
Qiaoyan Ding ◽  
Yu Zhang ◽  
Li Ma ◽  
Yong-gang Chen ◽  
Jin-hu Wu ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Therapeutic Target ◽  
Mapk Signaling ◽  
Immunofluorescence Assay ◽  
Gh3 Cells ◽  
Wild Type ◽  
Potential Therapeutic Target ◽  
Protein Expressions ◽  
P38α Mapk

Abstract Background The pathogenesis of prolactinomas has not been clarified yet. p38 MAPK signaling including p38α MAPK (MAPK14), p38β (MAPK11), p38γ (MAPK12) and p38δ (MAPK13) is related to the development and progression of many cancers. We sought to investigate the role of MAPK14 in prolactinomas.Methods Immunofluorescence assay was performed on the prolactin (PRL) and MAPK14 protein expressions of pituitary gland in C57BL/6 mice and human prolactinomas specimens. We analyzed the role of MAPK14 in prolactinomas using estradiol-induced model and DRD2-/- model in C57BL/6 wild-type (WT), MAPK14-/- , DRD2-/-MAPK14+/- mice. GH3 cells were transfected with different sets of MAPK14 siRNA, which to study MAPK14 and PRL protein expression in GH3.Results Immunofluorescenc assaye found that PRL and MAPK14 were co-locatied and increased significantly in the pituitary gland of estradiol-injected prolactinomas mice than in control mice. And the deficiency of MAPK14 significantly inhibited the tumor overgrowth, along with the PRL decrease in estradiol-induced mice. Furthermore, MAPK14 deficiency in DRD2-/-MAPK14+/- mice significantly inhibited the overgrowth of pituitary gland and PRL production and secretion than in DRD2-/- mice. And MAPK14 knockdown by siRNA inhibited PRL production in GH3 cells.Conclusion The results establish that MAPK14 plays a promoting role in the formation of prolactinomas, and validate MAPK14 as potential therapeutic target.

scholarly journals RIP1/RIP3/MLKL Mediates Myocardial Function Through Necroptosis in Experimental Autoimmune Myocarditis

2021 ◽  
Vol 8 ◽  
Author(s):  
Yujing Wu ◽  
Zhenzhong Zheng ◽  
Xiantong Cao ◽  
Qing Yang ◽  
Vikram Norton ◽  
...  
Keyword(s):  
Cell Death ◽  
Myocardial Function ◽  
Viral Myocarditis ◽  
Cardiac Myosin ◽  
Autoimmune Myocarditis ◽  
Potential Therapeutic Target ◽  
Inflammatory Infiltration ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apoptosis is long considered as the principal process of cell death in cardiomyocytes, but programmed necrosis or necroptosis is recently believed to play an important role in cardiomyocyte cell death. We investigated the role of necroptosis and its interdependency with other processes of cell death, autophagy, and apoptosis in a rat system of experimental autoimmune myocarditis (EAM). We successfully created a rat model system of EAM by injecting porcine cardiac myosin (PCM) and showed that in EAM, all three forms of cell death increase considerably, resulting in the deterioration of cardiac conditions with an increase in inflammatory infiltration in cardiomyocytes. To explore whether necroptosis occurs in EAM rats independent of autophagy, we treated EAM rats with a RIP1/RIP3/MLKL kinase-mediated necroptosis inhibitor, Necrostatin-1 (Nec-1). In Nec-1 treated rats, cell death proceeds through apoptosis but has no significant effect on autophagy. In contrast, autophagy inhibitor 3-Methyl Adenine (3-MA) increases necroptosis, implying that blockage of autophagy must be compensated through necroptosis. Caspase 8 inhibitor zVAD-fmk blocks apoptosis but increases both necroptosis and autophagy. However, all necroptosis, apoptosis, and autophagy inhibitors independently reduce inflammatory infiltration in cardiomyocytes and improve cardiac conditions. Since apoptosis or autophagy is involved in many important cellular aspects, instead of suppressing these two major cell death processes, Nec1 can be developed as a potential therapeutic target for inflammatory myocarditis.

scholarly journals Signaling through the Prostaglandin I2 Receptor IP Protects against Respiratory Syncytial Virus-Induced Illness

2004 ◽  
Vol 78 (19) ◽  
pp. 10303-10309 ◽  
Author(s):  
Koichi Hashimoto ◽  
Barney S. Graham ◽  
Mark W. Geraci ◽  
Garret A. FitzGerald ◽  
Karine Egan ◽  
...  
Keyword(s):  
Weight Loss ◽  
Respiratory Syncytial Virus ◽  
Bronchial Epithelium ◽  
Gamma Interferon ◽  
Wild Type ◽  
Prostaglandin I2 ◽  
Potential Therapeutic Target ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT The role of prostanoids in modulating respiratory syncytial virus (RSV) infection is unknown. We found that RSV infection in mice increases production of prostaglandin I2 (PGI2). Mice that overexpress PGI2 synthase selectively in bronchial epithelium are protected against RSV-induced weight loss and have decreased peak viral replication and gamma interferon levels in the lung compared to nontransgenic littermates. In contrast, mice deficient in the PGI2 receptor IP have exacerbated RSV-induced weight loss with delayed viral clearance and increased levels of gamma interferon in the lung compared to wild-type mice. These results suggest that signaling through IP has antiviral effects while protecting against RSV-induced illness and that PGI2 is a potential therapeutic target in the treatment of RSV.

scholarly journals Suppression of the Reactive Oxygen Response Alleviates Experimental Autoimmune Uveitis in Mice

2020 ◽  
Vol 21 (9) ◽  
pp. 3261 ◽  
Author(s):  
Sheng-Min Hsu ◽  
Chang-Hao Yang ◽  
Yu-Ti Teng ◽  
Hsien-Yang Tsai ◽  
Chieh-Yu Lin ◽  
...  
Keyword(s):  
Reactive Oxygen ◽  
Oxygen Species ◽  
Wild Type ◽  
Experimental Autoimmune Uveitis ◽  
Autoimmune Uveitis ◽  
Monocyte Chemoattractant ◽  
Tnf Α ◽  
Necrosis Factor ◽  
Experimental Autoimmune

Reactive oxygen species (ROS) are produced by host phagocytes and play an important role in antimicrobial actions against various pathogens. Autoimmune uveitis causes blindness and severe visual impairment in humans at all ages worldwide. However, the role of ROS in autoimmune uveitis remains unclear. We used ROS-deficient (Ncf1−/−) mice to investigate the role of ROS in experimental autoimmune uveitis (EAU). Besides, we also used the antioxidant N-acetylcysteine (NAC) treatment to evaluate the effect of suppression of ROS on EAU in mice. The EAU disease scores of Ncf1−/− mice were significantly lower than those of wild-type mice. EAU induction increased the levels of cytokines (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-12, IL-17, and tumor necrosis factor (TNF)-α) and chemokines (monocyte chemoattractant protein (MCP)-1) in the retinas of wild-type mice but not in those of Ncf1−/− mice. EAU induction enhanced the level of NF-κB activity in wild-type mice. However, the level of NF-κB activity in Ncf1−/− mice with EAU induction was low. Treatment with the antioxidant NAC also decreased the severity of EAU in mice with reduced levels of oxidative stress, inflammatory mediators, and NF-κB activation in the retina. We successfully revealed a novel role of ROS in the pathogenesis of EAU and suggest a potential antioxidant role for the treatment of autoimmune uveitis in the future.

scholarly journals Ablation of apoptosis-stimulating of p53 protein 1 protects mice from acute hepatic injury and dysfunction via NF-κB pathway in CCl4-induced hepatotoxicity

2021 ◽  
Vol 1 (1) ◽  
pp. 53-64
Author(s):  
Tolessa Muleta Daba ◽  
Xiang Huang ◽  
Timur Yagudin ◽  
Ying Yang ◽  
Jiangang Wang ◽  
...  
Keyword(s):  
Hepatic Injury ◽  
Acute Liver Injury ◽  
P53 Protein ◽  
Underlying Mechanism ◽  
Wild Type ◽  
Potential Therapeutic Target ◽  
Environmental Responses ◽  
And Oxidative Stress ◽  
Flood Flow

Abstract Acute liver injury (ALI) is characterized by apoptosis, inflammation, and oxidative stress, and pathogenic mechanism of ALI is poorly understood. Apoptosis-stimulating of p53 protein 1 (ASPP1) is involved in environmental responses, tumor growth, and NF-KB activity, which is of critical importance to ALI. However, the role of ASPP1 in ALI remains largely unexplored. The current study aimed to determine the role of ASPP1 in ALI induced by CCl4 and the underlying mechanism. ASPP1 expression was detected in wild type (WT) mice with ALI induced by CCl4. The function of ASPP1 in ALI induced by CCl4 was investigated using conventional knockout ASPP1 mice. ASPP1 expression significantly increased in ALI mice at 24 hours after CCl4 injection. Deletion of ASSP1 ameliorated apoptosis, inflammation, and necrosis in ALI relative to WT mice. In addition, deficiency of ASPP1 improved liver flood flow as well as ALT and AST levels. The levels of phosphorylated p65 and phosphorylated IκBα were lower in ASPP1-/- mice than in WT mice with ALI. These results implicate that deletion of ASPP1 may act via inhibition of the NF-κB pathway and protect mice from ALI, which may be a new potential therapeutic target for the treatment of ALI.

scholarly journals Regulatory Role of CD1d in Neurotropic Virus Infection

2008 ◽  
Vol 82 (20) ◽  
pp. 10279-10289 ◽  
Author(s):  
Ikuo Tsunoda ◽  
Tomoko Tanaka ◽  
Robert S. Fujinami
Keyword(s):  
Virus Infection ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Nkt Cells ◽  
Protective Role ◽  
Neurological Deficits ◽  
Interleukin 4 ◽  
Wild Type ◽  
The Central Nervous System

ABSTRACT The GDVII strain of Theiler's murine encephalomyelitis virus (TMEV) causes an acute fatal polioencephalomyelitis in mice. Infection of susceptible mice with the DA strain of TMEV results in an acute polioencephalomyelitis followed by chronic immune-mediated demyelination with virus persistence in the central nervous system (CNS); DA virus infection is used as an animal model for multiple sclerosis. CD1d-restricted natural killer T (NKT) cells can contribute to viral clearance and regulation of autoimmune responses. To investigate the role of CD1d in TMEV infection, we first infected CD1d-deficient mice (CD1−/−) and wild-type BALB/c mice with GDVII virus. Wild-type mice were more resistant to virus than CD1−/− mice (50% lethal dose titers: wild-type mice, 10 PFU; CD1−/− mice, 1.6 PFU). Wild-type mice had fewer viral antigen-positive cells with greater inflammation in the CNS than CD1−/− mice. Second, an analysis of DA virus infection in CD1−/− mice was conducted. Although both wild-type and CD1−/− mice had similar clinical signs during the first 2 weeks after infection, CD1−/− mice had an increase in neurological deficits over those observed in wild-type mice at 3 to 5 weeks after infection. Although wild-type mice had no demyelination, 20 and 60% of CD1−/− mice developed demyelination at 3 and 5 weeks after infection, respectively. TMEV-specific lymphoproliferative responses, interleukin-4 (IL-4) production, and IL-4/gamma interferon ratios were higher in CD1−/− mice than in wild-type mice. Thus, CD1d-restricted NKT cells may play a protective role in TMEV-induced neurological disease by alteration of the cytokine profile and virus-specific immune responses.

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