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(1) Peripheral Neuroimmunoendocrine Interactions: Contribution of TNFRp55 to the Circadian Synchronization of Progesterone and Cytokine Production in Joints of Mice in Late Pregnancy.[TOP]

Pubmed ID :30304732
Publication Date : //
Circadian rhythms are generated by the suprachiasmatic nucleus of the hypothalamus and involve rhythmic expression of clock genes and proteins. This rhythmicity is transferred to peripheral tissues by neural and hormonal signals. Late pregnancy is considered a state of inflammation which impacts on peripheral tissues such as joints. Tumor necrosis factor (TNF) mediates inflammatory and circadian responses through its p55 receptor (TNFRp55). Neuroimmunoendocrine interactions in joints have not been studied completely. The purpose of this study was to analyze these interactions, investigating the circadian rhythms of progesterone (Pg) and pro- and anti-inflammatory cytokines in the joints at the end of pregnancy (gestational day 18). Moreover, the impact of TNFRp55 deficiency on these temporal oscillations was explored.

Authors : Arias José L, Mayordomo Andrea C, Silva Juan E, Ragusa Juan A V, Rabinovich Gabriel A, Anzulovich Ana C, Di Genaro María S,

(2) A novel fusion protein attenuates collagen-induced arthritis by targeting interleukin 17A and tumor necrosis factor α.[TOP]

Pubmed ID :29803792
Publication Date : //
This study was undertaken to generate a novel dual targeting fusion protein (DTF), targeting tumor necrosis factor α (TNF-α) and interleukin 17A (IL-17A), and determine its anti-arthritis properties in vitro and in vivo. DTF consisted of an anti-IL-17A single chain variable fragment, a soluble TNF receptor 1, and an Fc fragment. Both clinical and histopathological evaluations suggest that DTF and etanercept can ameliorate collagen induced arthritis. However, the arthritis severity score of DTF-treated mice was lower than that of etanercept-treated mice. In addition, DTF was more potent than etanercept in decreasing the ratio of RANKL/OPG in the serum and rebalancing the population ratio of Treg/Th17 cells in the spleens. In vitro, IL-17A and TNF-α had synergistic effects in inducing the expression of inflammatory cytokines in fibroblast-like synoviocyte from RA patients (RA-FLS), human leukemia (THP-1), and rheumatoid synovial fibroblast (MH7A). IL-17A and TNF-α also had synergistic effects in inducing proliferation and migration of MH7A cells. However, we observed that DTF was more efficient than etanercept in suppressing these synergistic effects. Our results demonstrate that DTF is highly efficient in the treatment of arthritis and has the potential to overcome the limited therapeutic responses obtained with single cytokine neutralization.

Authors : Liu Zhihang, Song Liying, Wang Yunxin, Xu Pengfei, Guo Xiaochen, Yang Jiarui, Liu Han, Wang Yuyang, Wu Chao, Zhang Teng, Yu Dan, Opoku Yeboah Kwaku, Khoso Mir Hassan, Ren Guiping, Li Deshan,

(3) IL-12/23p40 overproduction by dendritic cells leads to an increased Th1 and Th17 polarization in a model of Yersinia enterocolitica-induced reactive arthritis in TNFRp55-/- mice.[TOP]

Pubmed ID :29494692
Publication Date : //
Dendritic cells (DCs) play critical functions in the initiation of immune responses. Understanding their role in reactive arthritis (ReA) will help delineate the pathogenesis of this arthropathy. In early studies, we detected IL-12/23p40 deregulation in Yersinia entercolitica (Ye)-induced ReA in TNFRp55-deficient (TNFRp55-/-) mice. In this study, we assessed the contribution of DCs in this overproduction. First, greater levels of IL-12/23p40, IFN-γand IL-17A were confirmed in supernatants of lipopolysaccharide (LPS)-stimulated TNFRp55-/-splenocytes obtained on arthritis onset (day 14 after Ye infection). Later, DCs were identified as a precise source of IL-12/23p40 since increased frequency of splenic IL-12/23p40+DCs was detected in TNFRp55-/- mice. After robust in vivo amplification of DCs by injection of Fms-like tyrosine kinase 3-Ligand (Flt3L)-transfected BL16 melanoma, DCs were purified. These cells recapitulated the higher production of IL-12/23p40 under TNFRp55deficiency. In agreement with these results, TNFRp55-/- DCs promoted Th1 and Th17 programs by co-culture with WT CD4+lymphocytes. A mechanistic study demonstrated that JNK and p38 MAPK pathways are involved in IL-12/23p40 overproduction in purified TNFRp55-/- DCs as well as in the JAWS II cell line. This deregulation was once again attributed to TNFRp55 deficiency since CAY10500, a specific inhibitor of this pathway, compromised TNF-mediated IL-12/23p40 control in LPS-stimulated WT DCs. Simultaneously, this inhibition reduced IL-10 production, suggesting its role mediating IL-12/23p40 regulation by TNFRp55 pathway. These results provide experimental data on the existence of a TNFRp55-mediated anti-inflammatory circuit in DCs. Moreover, these cells may be considered as a novel target in the treatment of ReA.

Authors : Mayordomo Andrea Constanza, Silva Juan Eduardo, Gorlino Carolina Virginia, Arias José Luis, Berón Walter, Di Genaro María Silvia,

(4) TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma.[TOP]

Pubmed ID :29273790
Publication Date : //
Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma. However, many patients do not display therapeutic response or eventually relapse. Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor α (TNF) antibodies. Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown. Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in mouse melanoma. Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers. Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens. This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients.

Authors : Bertrand Florie, Montfort Anne, Marcheteau Elie, Imbert Caroline, Gilhodes Julia, Filleron Thomas, Rochaix Philippe, Andrieu-Abadie Nathalie, Levade Thierry, Meyer Nicolas, Colacios Céline, Ségui Bruno,

(5) [TOP]

Pubmed ID :
Publication Date : //

Authors :

(6) Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency.[TOP]

Pubmed ID :28846096
Publication Date : //
Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.

Authors : Giampazolias Evangelos, Zunino Barbara, Dhayade Sandeep, Bock Florian, Cloix Catherine, Cao Kai, Roca Alba, Lopez Jonathan, Ichim Gabriel, Proïcs Emma, Rubio-Patiño Camila, Fort Loic, Yatim Nader, Woodham Emma, Orozco Susana, Taraborrelli Lucia, Peltzer Nieves, Lecis Daniele, Machesky Laura, Walczak Henning, Albert Matthew L, Milling Simon, Oberst Andrew, Ricci Jean-Ehrland, Ryan Kevin M, Blyth Karen, Tait Stephen W G,

(7) Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.[TOP]

Pubmed ID :28747340
Publication Date : //
TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/β-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, intestinal stem cell and progenitor cell Wnt/β-catenin signaling correlates with inflammation status. TNF-deficient () mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow (BM) chimera mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IECs. Wild-type→ BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/β-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/β-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced β-catenin activation in nontransformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together, these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/β-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.

Authors : Bradford Emily M, Ryu Stacy H, Singh Ajay Pal, Lee Goo, Goretsky Tatiana, Sinh Preetika, Williams David B, Cloud Amber L, Gounaris Elias, Patel Vihang, Lamping Olivia F, Lynch Evan B, Moyer Mary Pat, De Plaen Isabelle G, Shealy David J, Yang Guang-Yu, Barrett Terrence A,

(8) Transmembrane TNF-dependent uptake of anti-TNF antibodies.[TOP]

Pubmed ID :28323513
Publication Date : //
TNF-α (TNF), a pro-inflammatory cytokine is synthesized as a 26 kDa protein, anchors in the plasma membrane as transmembrane TNF (TmTNF), and is subjected to proteolysis by the TNF-α converting enzyme (TACE) to release the 15 kDa form of soluble TNF (sTNF). TmTNF and sTNF interact with 2 distinct receptors, TNF-R1 (p55) and TNF-R2 (p75), to mediate the multiple biologic effects of TNF described to date. Several anti-TNF biologics that bind to both forms of TNF and block their interactions with the TNF receptors are now approved for the treatment of a variety of immune-mediated diseases. Several reports suggest that binding of anti-TNFs to TmTNF delivers an outside-to-inside 'reverse' signal that may also contribute to the efficacy of anti-TNFs. Some patients, however, develop anti-TNF drug antibody responses (ADA or immunogenicity). Here, we demonstrate biochemically that TmTNF is transiently expressed on the surface of lipopolysaccharide-stimulated primary human monocytes, macrophages, and monocyte-derived dendritic cells (DCs) and expression of TmTNF on the cell surface is enhanced following treatment of cells with TAPI-2, a TACE inhibitor. Importantly, binding of anti-TNFs to TmTNF on DCs results in rapid internalization of the anti-TNF/TmTNF complex first into early endosomes and then lysosomes. The internalized anti-TNF is processed and anti-TNF peptides can be eluted from the surface of DCs. Finally, tetanus toxin peptides fused to anti-TNFs are presented by DCs to initiate T cell recall proliferation response. Collectively, these observations may provide new insights into understanding the biology of TmTNF, mode of action of anti-TNFs, biology of ADA response to anti-TNFs, and may help with the design of the next generation of anti-TNFs.

Authors : Deora Arun, Hegde Subramanya, Lee Jacqueline, Choi Chee-Ho, Chang Qing, Lee Cheryl, Eaton Lucia, Tang Hua, Wang Dongdong, Lee David, Michalak Mark, Tomlinson Medha, Tao Qingfeng, Gaur Nidhi, Harvey Bohdan, McLoughlin Shaun, Labkovsky Boris, Ghayur Tariq,

(9) Inflammatory 'double hit' model of temporomandibular joint disorder with elevated CCL2, CXCL9, CXCL10, RANTES and behavioural hypersensitivity in TNFR1/R2-/- mice.[TOP]

Pubmed ID :28318085
Publication Date : //
Patients with temporomandibular joint disorders (TMD), reactive arthritis and rheumatoid arthritis often have combined etiology of hereditary and microenvironmental factors contributing to joint pain. Multiple clinical and animal studies indicate 'double-hit' inflammatory insults can cause chronic inflammation. The first inflammatory insult primes the immune system and subsequent insults elicit amplified responses. The present 'double hit' study produced a chronic orofacial pain model in mice with genetic deletion of both TNFα receptors (TNFR1/R2-/-), investigating the main nociceptive signalling pathways in comparisons to wild type mice.

Authors : McIlwrath S L, Nesemeier R, Ma F, Oz H S, Zhang L, Westlund K N,

(10) A trimeric structural fusion of an antagonistic tumor necrosis factor-α mutant enhances molecular stability and enables facile modification.[TOP]

Pubmed ID :28235800
Publication Date : //
Tumor necrosis factor-α (TNF) exerts its biological effect through two types of receptors, p55 TNF receptor (TNFR1) and p75 TNF receptor (TNFR2). An inflammatory response is known to be induced mainly by TNFR1, whereas an anti-inflammatory reaction is thought to be mediated by TNFR2 in some autoimmune diseases. We have been investigating the use of an antagonistic TNF mutant (TNFR1-selective antagonistic TNF mutant (R1antTNF)) to reveal the pharmacological effect of TNFR1-selective inhibition as a new therapeutic modality. Here, we aimed to further improve and optimize the activity and behavior of this mutant protein both and Specifically, we examined a trimeric structural fusion of R1antTNF, formed via the introduction of short peptide linkers, as a strategy to enhance bioactivity and molecular stability. By comparative analysis with R1antTNF, the trimeric fusion, referred to as single-chain R1antTNF (scR1antTNF), was found to retain molecular properties of receptor selectivity and antagonistic activity but displayed a marked increase in thermal stability. The residence time of scR1antTNF was also significantly prolonged. Furthermore, molecular modification using polyethylene glycol (PEG) was easily controlled by limiting the number of reactive sites. Taken together, our findings show that scR1antTNF displays enhanced molecular stability while maintaining biological activity compared with R1antTNF.

Authors : Inoue Masaki, Ando Daisuke, Kamada Haruhiko, Taki Shintaro, Niiyama Mayumi, Mukai Yohei, Tadokoro Takashi, Maenaka Katsumi, Nakayama Taisuke, Kado Yuji, Inoue Tsuyoshi, Tsutsumi Yasuo, Tsunoda Shin-Ichi,