Related Experiment Video
Updated: Apr 28, 2026
08:41
Visualization of Inflammatory Caspases Induced Proximity in Human Monocyte-Derived Macrophages
Published on: April 6, 2022
2.2K
A critical role for human caspase-4 in endotoxin sensitivity
Yuji Kajiwara1, Tamar Schiff2, Georgios Voloudakis1
1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
Journal of Immunology (Baltimore, Md. : 1950)
|June 1, 2014
Summary
Human caspase-4 significantly increases endotoxin sensitivity and lethality in mice. This inflammatory caspase may explain why humans are more sensitive to endotoxins than rodents, offering new therapeutic targets.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Endotoxin response is critical in sepsis and metabolic endotoxemia.
- Humans exhibit greater endotoxin sensitivity than mice.
- Inflammatory caspases mediate endotoxin response in mice; human caspase-4 is absent in mice.
Purpose of the Study:
- To investigate the role of human caspase-4 in endotoxin sensitivity.
- To develop a mouse model for studying human caspase-4 function.
Main Methods:
- Created transgenic mice expressing human caspase-4.
- Administered lipopolysaccharide (LPS) to challenge mice.
- Analyzed cytokine secretion and lethality.
- Utilized bone marrow-derived macrophages to study caspase activation.
Main Results:
- Caspase-4 transgenic mice showed heightened sensitivity to endotoxins, with increased cytokine release and mortality.
- Caspase-4 promoted caspase-1 activation and IL-1β/IL-18 secretion without requiring inflammasome assembly signals.
- This suggests a unique human mechanism for regulating caspase-1 activity.
Conclusions:
- Human caspase-4 significantly enhances endotoxin sensitivity and lethality.
- Caspase-4 may explain higher human endotoxin sensitivity compared to rodents.
- Targeting caspase-4 offers potential therapeutic strategies for inflammatory conditions like sepsis.
Related Concept Videos
01:24Caspases
8.6K
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
8.6K
01:17The Extrinsic Apoptotic Pathway
6.2K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
6.2K
01:31The Intrinsic Apoptotic Pathway
6.2K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.2K
01:16Transduction
3.0K
Among the three main modes of HGT—transformation, conjugation, and transduction—transduction is unique in that it is mediated by bacteriophages, or bacterial viruses.Transduction occurs in two ways. Generalized transduction occurs during the lytic cycle of a bacteriophage infection. In this process, bacteriophages infect bacterial cells, replicate within them, and ultimately cause cell lysis, releasing newly assembled virions. Occasionally, random fragments of the bacterial genome...
3.0K
01:30Other Stress Responses in Bacteria
582
Bacteria have global regulatory systems that control several types of stress mechanisms. These include Pho regulon and the heat shock response, which are essential systems for environmental adaptation, such as nutrient limitation and proteotoxic stress. The Pho regulon and the heat shock response exemplify bacterial resilience, enabling rapid adaptation to fluctuating environmental conditions.Pho RegulonBacteria require phosphorus for essential cellular processes, including nucleic acid...
582
01:12Bacterial Toxins
139
Bacterial toxins are sophisticated virulence factors that enable pathogenic bacteria to interact with, invade, and damage host tissues. These toxins fall broadly into two types: protein exotoxins, which are secreted into the environment and target specific host receptors, and lipopolysaccharide endotoxins, which are structural components of the bacterial outer membrane released primarily during bacterial lysis or membrane shedding. Exotoxins generally act more selectively, binding to cell...
139