scholarly journals The Effects of Microtubule Stabilizing Drugs on Macrophage Immune-Mediated Endocytosis

2021 ◽  
Author(s):  
◽  
Praneta Joshi
Keyword(s):  
Bacterial Infections ◽  
Normal Function ◽  
Proliferating Cells ◽  
Necrosis Factor Alpha ◽  
Bacterial Killing ◽  
Microtubule Stabilization ◽  
Macrophage Activity ◽  
Cancer Chemotherapeutics ◽  
Immune Mediated ◽  
Factor Alpha

<p>Microtubule stabilizing drugs (MSD) bind and stabilize microtubules, thus inhibiting their normal function. MSD exhibit anti-mitotic effects which makes them attractive as cancer chemotherapeutics and much of existing research has focused on these effects in proliferating cells. In contrast, we are interested in assessing the effects of microtubule stabilization on non-proliferating cells, such as macrophages, to determine potential mitosis-independent actions of MSD on microtubule function. Thus, we investigated the effects of MSD on macrophage receptor-mediated endocytosis of low density lipoproteins (LDL) and found no significant effect on the ability of paclitaxel-treated macrophages to endocytose LDL. Alterations to macrophage phagocytic and killing efficiency due to treatment with paclitaxel, peloruside or docetaxel, as well as the recently discovered compounds, ixabepilone, mycothiazole, and zampanolide were investigated. Treatment with paclitaxel, peloruside or docetaxel did not significantly inhibit phagocytosis or killing of bacteria. Results from confocal microscopy suggest that paclitaxel alters phagocytic kinetics in macrophages. Respectively, zampanolide and mycothiazole significantly inhibited macrophage bactericidal and killing ability, while Ixabepilone enhanced bacterial killing. MSD treatment also altered production of tumor necrosis factor alpha (TNF-a) and nitric oxide (NO) during bacterial killing. Optimal activation of macrophages with IFN-y did not alter the effects of MSD. Taken together, these results suggest that MSD have multiple immunomodulatory effects unrelated to their anti-mitotic effects. The data suggests that during MSD treatment, macrophage activity maybe altered or impaired, thus modifying the ability of patients to fight off bacterial infections.</p>

scholarly journals The Effects of Microtubule Stabilizing Drugs on Macrophage Immune-Mediated Endocytosis

2021 ◽  
Author(s):  
◽  
Praneta Joshi
Keyword(s):  
Bacterial Infections ◽  
Normal Function ◽  
Proliferating Cells ◽  
Necrosis Factor Alpha ◽  
Bacterial Killing ◽  
Microtubule Stabilization ◽  
Macrophage Activity ◽  
Cancer Chemotherapeutics ◽  
Immune Mediated ◽  
Factor Alpha

<p>Microtubule stabilizing drugs (MSD) bind and stabilize microtubules, thus inhibiting their normal function. MSD exhibit anti-mitotic effects which makes them attractive as cancer chemotherapeutics and much of existing research has focused on these effects in proliferating cells. In contrast, we are interested in assessing the effects of microtubule stabilization on non-proliferating cells, such as macrophages, to determine potential mitosis-independent actions of MSD on microtubule function. Thus, we investigated the effects of MSD on macrophage receptor-mediated endocytosis of low density lipoproteins (LDL) and found no significant effect on the ability of paclitaxel-treated macrophages to endocytose LDL. Alterations to macrophage phagocytic and killing efficiency due to treatment with paclitaxel, peloruside or docetaxel, as well as the recently discovered compounds, ixabepilone, mycothiazole, and zampanolide were investigated. Treatment with paclitaxel, peloruside or docetaxel did not significantly inhibit phagocytosis or killing of bacteria. Results from confocal microscopy suggest that paclitaxel alters phagocytic kinetics in macrophages. Respectively, zampanolide and mycothiazole significantly inhibited macrophage bactericidal and killing ability, while Ixabepilone enhanced bacterial killing. MSD treatment also altered production of tumor necrosis factor alpha (TNF-a) and nitric oxide (NO) during bacterial killing. Optimal activation of macrophages with IFN-y did not alter the effects of MSD. Taken together, these results suggest that MSD have multiple immunomodulatory effects unrelated to their anti-mitotic effects. The data suggests that during MSD treatment, macrophage activity maybe altered or impaired, thus modifying the ability of patients to fight off bacterial infections.</p>

scholarly journals Paradoxical Psoriasis Induced by Anti-TNFα Treatment: Evaluation of Disease-Specific Clinical and Genetic Markers

2020 ◽  
Vol 21 (21) ◽  
pp. 7873
Author(s):  
Agostino Bucalo ◽  
Federica Rega ◽  
Arianna Zangrilli ◽  
Valentina Silvestri ◽  
Virginia Valentini ◽  
...  
Keyword(s):  
Rare Allele ◽  
Paradoxical Effect ◽  
Nucleotide Polymorphisms ◽  
Necrosis Factor Alpha ◽  
Genetic Characteristics ◽  
Immune Mediated ◽  
Tnf Α ◽  
Bowel Diseases ◽  
Factor Alpha ◽  
Disease Specific

Paradoxical psoriasis (PP) may occur during treatment with anti-tumor necrosis factor-alpha (TNF-α) drugs in various chronic immune-mediated diseases, mainly inflammatory bowel diseases (IBD) and psoriasis. In this study, clinical and genetic characteristics of PP arising in IBD and psoriatic patients were investigated to identify disease-specific markers of the paradoxical effect. A total of 161 IBD and psoriatic patients treated with anti-TNF-α drugs were included in the study. Of these patients, 39 developed PP. All patients were characterized for the main clinical–pathologic characteristics and genotyped for six candidate single nucleotide polymorphisms (SNPs) selected for their possible role in PP susceptibility. In IBD patients, the onset of PP was associated with female sex, presence of comorbidities, and use of adalimumab. IBD patients with PP had a higher frequency of the TNF-α rs1799964 rare allele (p = 0.006) compared with cases without the paradoxical effect, and a lower frequency of the human leucocyte antigen (HLA)-Cw06 rs10484554 rare allele (p = 0.03) compared with psoriatic patients with PP. Overall, these findings point to specific clinical and genetic characteristics of IBD patients with PP and provide data showing that genetic variability may be related to the paradoxical effect of anti-TNF-α drugs with possible implications into clinical practice.

scholarly journals Pathological findings in central nervous system demyelination associated with infliximab

2019 ◽  
Vol 26 (9) ◽  
pp. 1124-1129 ◽  
Author(s):  
Alicja Kalinowska-Lyszczarz ◽  
Mahboobeh Fereidan-Esfahani ◽  
Yong Guo ◽  
Claudia F Lucchinetti ◽  
W Oliver Tobin
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tnf Alpha ◽  
Infliximab Treatment ◽  
Necrosis Factor Alpha ◽  
Immune Mediated ◽  
Central Nervous System Demyelination ◽  
Factor Alpha ◽  
Cns Demyelination ◽  
Necrosis Factor

Background: Tumor necrosis factor alpha (TNF-alpha) inhibitors, such as infliximab, are commonly used to treat rheumatoid arthritis (RA) and other immune-mediated disorders. Objective: To determine whether infliximab-associated central nervous system (CNS) demyelination can be differentiated from multiple sclerosis (MS). Methods: We present a case of pathologically proven CNS demyelination in a patient treated with infliximab and describe clinical–radiographic–neuropathological findings. Putative mechanisms of TNF-alpha inhibitor-associated CNS demyelination are described. Results and conclusion: Infliximab treatment is associated with CNS inflammatory demyelinating activity, which is histopathologically indistinguishable from MS.

scholarly journals Febrile Core Temperature Is Essential for Optimal Host Defense in Bacterial Peritonitis

2000 ◽  
Vol 68 (3) ◽  
pp. 1265-1270 ◽  
Author(s):  
Qinqqi Jiang ◽  
Alan S. Cross ◽  
Ishwar S. Singh ◽  
T. Timothy Chen ◽  
Rose M. Viscardi ◽  
...  
Keyword(s):  
Core Temperature ◽  
Host Defense ◽  
Bacterial Infections ◽  
Bacterial Load ◽  
Cytokine Expression ◽  
Microbial Pathogens ◽  
Necrosis Factor Alpha ◽  
Bacterial Peritonitis ◽  
Tnf Α ◽  
Factor Alpha

ABSTRACT Fever, a nonspecific acute-phase response, has been associated with improved survival and shortened disease duration in infections, but the mechanisms of these beneficial responses are poorly understood. We previously reported that increasing core temperature of bacterial endotoxin (LPS)-challenged mice to the normal febrile range modified expression of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and IL-6, three cytokines critical to mounting an initial defense against microbial pathogens, but survival was not improved in the warmer animals. We speculated that our inability to show a survival benefit of optimized cytokine expression in the warmer animals reflected our use of LPS, a nonreplicating agonist, rather than an infection with viable pathogens. The objective of this study was to determine if increasing murine core temperature altered cytokine expression and improved survival in an experimental bacterial peritonitis model. We showed that housing mice at 35.5°C rather than 23°C increased core temperature from 36.5 to 37.5°C to 39.2 to 39.7°C, suppressed plasma TNF-α expression for the initial 48 h, delayed gamma interferon expression, improved survival, and reduced the bacterial load in mice infected with Klebsiella pneumoniae peritonitis. We showed that the reduced bacterial load was not caused by a direct effect on bacterial proliferation and probably reflected enhanced host defense. These data suggest that the increase in core temperature that occurs during bacterial infections is essential for optimal antimicrobial host defense.

scholarly journals The characterization of a humanized rabbit anti-TNFα monoclonal antibody

2019 ◽  
Author(s):  
Chao Wang ◽  
Xianpu Ni ◽  
Ying Liu ◽  
Zheng Jin ◽  
Huanzhang Xia
Keyword(s):  
Specific Binding ◽  
Positive Control ◽  
Negative Control ◽  
Necrosis Factor Alpha ◽  
Neutralizing Activity ◽  
Immune Mediated ◽  
Factor Alpha ◽  
Dose Dependent

Tumor necrosis factor alpha (TNFα) is now regarding as a key role in the pathogenesis of immune-mediated disease such as Rheumatoid arthritis (RA), Crohn's Disease, Psoriatic arthritis and Plaque Psoriasis. HERE we have successfully developed an anti-hTNFα monoclonal rabbit antibody(HZ3M) with high binding and neutralizing activity based on RabMAbs platform. Rabbit hybridomas, immunized subcutanrously with 0.4 mg human TNFα, were generated from the rabbit splenocytes and a total of 142 hybridoma clones with specific binding to human TNFa were obtained. The anti-TNFa RabMAbs showed better neutralizing activity and higher antigen binding affinity compared to Humira and Remicade, the elimination phase half-life 58.2h respectively. In vivo efficay studies, normal mice or human TNF-alpha transgenic mice were injected with 1.0 mg/kg Humira (positive control), HZ3M at 0.33?1.0 or 3.0 mg/kg, or solvent (negative control), showed that HZ3M is able to bind and neutralize hTNFα in transgenic and normal mice as well as normal rabbits.Clearly dose-dependent response can be determined. Compared to marketed anti-TNFa drug Humira, the efficacy of HZ3M is seems to show significant longer holding time.Our observations indicate that the HZ3M derived from RabMAb preclinical safety study, and might have a therapeutic role in RA treatment.

TNF-α and IL-6: The Link between Immune and Bone System

2020 ◽  
Vol 21 (3) ◽  
pp. 213-227 ◽  
Author(s):  
Tiantian Wang ◽  
Chengqi He
Keyword(s):  
Immune Responses ◽  
Macrophage Activation ◽  
Bone Diseases ◽  
Necrosis Factor Alpha ◽  
Immune Mediated ◽  
Pathogenic Factors ◽  
Tnf Α ◽  
Proliferation And Differentiation ◽  
Factor Alpha ◽  
Necrosis Factor

Osteoimmunology is a new subject which focuses on the communication between the immune and the skeletal systems. Both the immune system and bone communicate with each other. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) play important roles in immune responses and bone metabolism. TNF-α and IL-6 enhance macrophage activation and antigen presentation, as well as regulating immunity through different mechanisms. A variety of groups have reported that TNF-α suppresses osteoblasts activity at some stages of differentiation and stimulates osteoclast proliferation and differentiation. In contrast, IL-6 mediates the actions of osteoblasts and osteoclasts through sophisticated mechanisms, which reflect dual effects. Both TNF-α and IL-6 can mediate the activity of osteocytes. Furthermore, both TNF-α and IL-6 are important pathogenic factors related to immune-mediated bone diseases including rheumatoid arthritis and postmenopausal osteoporosis. This review will discuss the contradictory findings concerning TNF-α and IL-6 in osteoimmunology and their potential for clinical application.

scholarly journals The Coincidence of Necrotizing Enterocolitis and Rotavirus Infections and Potential Associations with Cytokines

2012 ◽  
Vol 23 (4) ◽  
pp. e103-e105 ◽  
Author(s):  
Efsun Sızmaz ◽  
Mehmet Satar ◽  
Ferda Özlü ◽  
Akgün Yaman ◽  
Hacer Yapıcıoğlu Yıldızdaş ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Necrotizing Enterocolitis ◽  
Tumour Necrosis ◽  
Bacterial Infections ◽  
Gastrointestinal Disease ◽  
Antigen Detection ◽  
Tumour Necrosis Factor Alpha ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease in neonatal intensive care units. Although the pathogenesis of NEC remains unclear, evidence suggests that infections, especially bacterial infections, may play an important role. Viral infections may also result in NEC. Several outbreaks of NEC associated with rotaviruses have been described previously.OBJECTIVE: To investigate the association between rotavirus (RV) and serum interleukin (IL)-6 and IL-8 levels in infants with NEC.METHODS: RV infections were prospectively studied using antigen detection in the stools of 31 infants with NEC. Additionally, serum levels of IL-6, IL-8 and tumour necrosis factor-alpha were tested using micro-ELISA at 0 h and 48 h after diagnosis of NEC.RESULTS: Fecal specimens from 13 infants were positive, while fecal specimens from 18 infants were negative for RV according to antigen detection (RV+ and RV− groups, respectively). The mortality rate and the severity of NEC were not significantly different between the RV+ and RV− groups. IL-6 levels at 0 h and 48 h after diagnosis of NEC in RV+ infants were lower compared with RV− infants, while IL-8 levels were greater at 0 h and 48 h after diagnosis of NEC in RV+ infants compared with RV− infants.CONCLUSION: A high prevalence of RV infection in neonates with NEC was found. Decreased IL-6 levels and increased IL-8 and tumour necrosis factor-alpha levels in RV+ neonates with NEC suggests a role for RV in NEC.

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