Disease relevance of Casp4

• Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic shock response [1].
• We show here that the expression of caspase-11 is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease [2].
• Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination [3].
• Transient global ischemia in rats also induced caspase-11 expression and IL-1beta production in hippocampus supporting our in vitro findings [4].
• Caspase-11 mediates inflammatory dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease [5].

High impact information on Casp4

• Furthermore, we found that pro-caspase-11 physically interacts with pro-ICE in cells, and the expression of casp-11 is essential for activation of ICE [6].
• Generation of Interleukin (IL)-1beta via cleavage of its proform requires the activity of caspase-1 (and caspase-11 in mice), but the mechanism involved in the activation of the proinflammatory caspases remains elusive [7].
• Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions [3].
• Furthermore, the induction of caspase-11 was evident in the ischemic brains of wild-type mice, and OLGs exhibited resistance to brain ischemia in mice deficient in caspase-11, suggesting that caspase-11 is critically implicated in the mechanism(s) underlying ischemia-induced OLG death [8].
• Using a positional scanning combinatorial library method, we found that the optimal cleavage site of caspase-11 was (I/L/V/P)EHD, similar to that of upstream caspases such as caspase-8 and -9 [9].

Chemical compound and disease context of Casp4

• The mRNA and proteins of ich-3 are dramatically induced in vivo upon stimulation with lipopolysaccharide, an inducer of septic shock [10].
• These findings suggest that while caspase-11 activation occurs in response to melphalan, it does not have a primary role in the pathogenesis of intestinal mucositis [11].

Biological context of Casp4

• Transient transfections with caspase-11 promoter-luciferase reporter constructs and deletion/mutation analysis revealed an essential role for NF-kappaB binding in the up-regulation of caspase-11 in response to LPS [12].
• Caspase-11 gene expression in response to lipopolysaccharide and interferon-gamma requires nuclear factor-kappa B and signal transducer and activator of transcription (STAT) 1 [12].
• OLGs from caspase-11-deficient mice were highly resistant to the cell death induced by cytotoxic cytokines [3].
• Here, we cloned the rat homolog of caspase-11, and investigated its inducibility by inflammatory stimuli and signal transduction pathways involved [13].
• This phenotype is likely due to failed cytokine processing known to occur in caspase-11 mutants since neonatal female mice lacking both interleukin (IL)-1alpha and IL-1beta also exhibit a reduced endowment of primordial follicles [14].

Anatomical context of Casp4

• We demonstrate here that in addition to its defect in cytokine maturation, caspase-11-deficient mice have a reduced number of apoptotic cells and a defect in caspase-3 activation after middle cerebral artery occlusion (MCAO), a mouse model of stroke [9].
• Here, we describe the identification and characterization of wedelolactone, a natural compound that inhibits LPS-induced caspase-11 expression in cultured cells by inhibiting NF-kappaB-mediated transcription [15].
• Here we show that cathepsin B is not involved in activation of caspase-11 induced by lipopolysaccharide (LPS) and subsequent maturation of interleukin (IL)-1beta in macrophages [16].
• Inflammatory induction of caspase-11 in astrocytes may play an important role in both inflammatory responses involving these cells and auto-regulatory apoptosis of activated astrocytes in inflammatory sites [13].
• The expression of caspase-11 was strongly induced at both mRNA and protein levels by inflammatory stimuli such as lipopolysaccharide (LPS), interferon-gamma, and tumor necrosis factor-alpha in C6 rat glial cells as well as primary astrocytes [13].

Associations of Casp4 with chemical compounds

• Our results indicate that the neurotoxic effects of LPS on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and caspase-11 expression in mice [17].
• Caspase-11 was also induced by such ER stress inducers as thapsigargin or tunicamycin [18].
• Caspase-11 (Cas11) is a cysteine protease involved in programmed cell death and cytokine maturation [19].
• Based on our previous findings that activation-induced cell death (AICD) of microglia occurs through two separate pathways (NO-dependent pathway and caspase-11-dependent pathway), our current results suggest that baicalein selectively inhibits the NO-dependent apoptotic pathway of activated microglia by suppressing cytotoxic NO production [20].
• Oligodendrocytes from caspase-11-deficient mice are partially resistant to TNF-induced OLG cell death [21].

Regulatory relationships of Casp4

• Cathepsin B has previously been shown to proteolytically activate the proinflammatory caspase-11 in vitro [16].
• Inhibition of both NO synthesis and caspase-11 completely blocked LPS/IFNgamma-induced cytotoxicity [22].

Other interactions of Casp4

• Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions [9].
• Furthermore, we show that caspase-11-mediated apoptosis under septic condition is Bid-independent [1].
• In addition, we provide biochemical evidence that other apoptosis initiator caspases (caspase-2 and -10) as well as a procaspase involved in inflammation (murine caspase-11) are also activated by oligomerization [23].
• Cathepsin B-mediated activation of the proinflammatory caspase-11 [24].
• Hypoxic induction of caspase-11 was observed in both mRNA and protein levels, and was mediated through p38 mitogen-activated protein kinase pathway [4].

References