Phenotypes Associated with This Genotype

Genotype
MGI:3574053

• Allelic Composition: Casp1^tm1Sesh/Casp1^tm1Sesh; Casp4^del/Casp4^del
• Genetic Background: involves: 129S2/SvPas * C57BL/6

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

neoplasm

neoplasm ( J:22964 , J:40691 )

N • homozygotes are viable and healthy with no signs of histological abnormalities in major organs; no spontaneous tumors are detected until the age of 25 weeks (J:22964)

N • homozygotes remain tumor-free at the age of 18 months (J:40691)

cellular

cellular phenotype ( J:22964 , J:40691 )

N • macrophages and thymocytes from mutant mice retain their capacity to undergo apoptosis upon ex vivo stimulation by several different signals (J:22964)

N • in response to ATP, mutant peritoneal macrophages undergo normal apoptosis relative to wild-type (J:40691)

N • in response to dexamethasone, aging or gamma irradiation, thymocytes from young homozygotes undergo normal apoptosis relative to wild-type (J:40691)

N • in response to LPS and D-galactosamine, homozygotes undergo normal TNF-induced hepatocyte apoptosis and show normal kinetics of death from hepatic failure relative to wild-type mice (J:40691)

abnormal apoptosis ( J:80568 )

• mutant peripheral blood neutrophils display retarded constitutive apoptosis relative to wild-type neutrophils

• mutant peripheral blood neutrophils show no LPS-mediated inhibition of apoptosis but remain susceptible to Fas-mediated apoptosis

decreased T cell apoptosis ( J:40691 )

• in vitro, thymocytes from young homozygotes are resistant to Fas-induced apoptosis as measured by cell viability

decreased neuron apoptosis ( J:88212 )

• cultured cerebrocortical neurons from homozygotes are highly resistant to oxygen/glucose deprivation (OGD)-induced neuronal cell death, showing only 50% of lactate dehydrogenase release relative to wild-type neurons

• also, mutant neurons are highly resistant to Ripk2-mediated cell death; transfecting caspase-1 into mutant neurons restores sensitivity to Ripk2-induced apoptosis

• notably, cultured neurons show inhibition of OGD-mediated processing of various members of the caspase pathway, cleavage of Bid, and hypoxia-associated loss of mitochondrial transmembrane potential; in vivo, these findings are confirmed in a cerebral ischemia model

abnormal cell migration ( J:68644 )

• in homozygotes lacking bioactive IL-1beta, IL-18 fails to induce the expected migration of epidermal Langerhans cells to draining lymph nodes following skin sensitization; as a result, immunostimulatory dendritic cells fail to accumulate in regional lymph nodes resulting in impaired initiation of cutaneous immune responses

hematopoietic system

hematopoietic system phenotype ( J:22964 )

N • homozygotes exhibit normal numbers of leukocytes, erythrocytes, and platelets in peripheral blood

N • freshly isolated mutant thymuses, spleens and lymph nodes contain a normal % of various T cell subsets and B cells relative to wild-type

decreased T cell apoptosis ( J:40691 )

• in vitro, thymocytes from young homozygotes are resistant to Fas-induced apoptosis as measured by cell viability

abnormal neutrophil physiology ( J:80568 )

• in addition to delayed apoptosis, mutant neutrophils show absence of LPS-stimulated IL-1beta production relative to wild-type

• in response to LPS-mediated acute lung injury, homozygotes show significantly increased total and percent neutrophil counts at 24 and 48 h; however, these numbers decline to wild-type levels by 72 h suggesting a delay in inflammatory neutrophil apoptosis

abnormal macrophage physiology ( J:22964 )

• ex vivo, thioglycollate-elicited peritoneal macrophages stimulated with LPS and ATP are defective in IL-1beta processing and release

immune system

immune system phenotype ( J:40691 )

N • in homozygotes, the % of B lymphocytes and the various T lymphocyte subsets found in mutant thymuses, spleens and lymph nodes appear unaffected relative to wild-type

N • the size and lymphocyte counts in these lymphoid organs appear normal; myeolopoiesis remains unaffected

decreased T cell apoptosis ( J:40691 )

• in vitro, thymocytes from young homozygotes are resistant to Fas-induced apoptosis as measured by cell viability

abnormal neutrophil physiology ( J:80568 )

• in addition to delayed apoptosis, mutant neutrophils show absence of LPS-stimulated IL-1beta production relative to wild-type

• in response to LPS-mediated acute lung injury, homozygotes show significantly increased total and percent neutrophil counts at 24 and 48 h; however, these numbers decline to wild-type levels by 72 h suggesting a delay in inflammatory neutrophil apoptosis

abnormal macrophage physiology ( J:22964 )

• ex vivo, thioglycollate-elicited peritoneal macrophages stimulated with LPS and ATP are defective in IL-1beta processing and release

decreased circulating interleukin-1 alpha level ( J:22964 )

• LPS-treated mice show a 5-fold decrease in IL-1alpha levels in vivo

decreased circulating interleukin-1 beta level ( J:22964 )

• in vivo, homozygous males injected with a high dose of LPS display undetectable levels of mature IL-1beta in their plasma; females are slightly less affected

decreased circulating interleukin-6 level ( J:22964 )

• after injection with a high dose of LPS, homozygotes display a moderate reduction in IL-6 levels relative to wild-type mice

decreased circulating tumor necrosis factor level ( J:22964 )

• after injection with a high dose of LPS, homozygotes display a moderate reduction in TNF levels relative to wild-type mice

decreased interleukin-1 alpha secretion ( J:22964 )

• surprisingly, homozygous males are also defective in IL-1alpha production, with macrophages releasing only 20-25% of wild-type IL-1alpha levels after stimulation with LPS and ATP ex vivo

decreased interleukin-1 beta secretion ( J:22964 , J:88212 )

• homozygotes are impaired in their capacity to produce mature IL-1beta (J:22964)

• ex vivo, mutant peritoneal macrophages stimulated with LPS and ATP release less that 1% of wild-type IL-1beta levels; however, no decrease in pro-IL-1beta synthesis or release is detected (J:22964)

• in culture, mutant cortical neurons exhibit inhibition of hypoxia-mediated generation of mature IL-1beta (J:88212)

abnormal inflammatory response ( J:80568 )

• in response to LPS-mediated acute lung injury, homozygotes exhibit a prolonged neutrophilic inflammatory response and evidence of caspase-1-independent IL-1beta production in the lung

decreased susceptibility to endotoxin shock ( J:22964 , J:40691 )

• strikingly, homozygotes are significantly resistant to the lethal effects of endotoxic shock after a high dose of LPS (J:22964)

• whereas all LPS-treated wild-type mice die within 30 hours after injection, all homozygotes survive for >45 hours, with only 30% of mutants dying during the next 5 days (J:22964)

reproductive system

reproductive system phenotype ( J:22964 , J:40691 )

N • homozygotes are fertile and produce a normal litter size relative to wild-type (J:22964)

N • in addition, post-lactation involution of mammary glands remains grossly normal in mutant post-partum females (J:22964)

N (J:40691)

nervous system

decreased neuron apoptosis ( J:88212 )

• cultured cerebrocortical neurons from homozygotes are highly resistant to oxygen/glucose deprivation (OGD)-induced neuronal cell death, showing only 50% of lactate dehydrogenase release relative to wild-type neurons

• also, mutant neurons are highly resistant to Ripk2-mediated cell death; transfecting caspase-1 into mutant neurons restores sensitivity to Ripk2-induced apoptosis

• notably, cultured neurons show inhibition of OGD-mediated processing of various members of the caspase pathway, cleavage of Bid, and hypoxia-associated loss of mitochondrial transmembrane potential; in vivo, these findings are confirmed in a cerebral ischemia model

decreased susceptibility to ischemic brain injury ( J:69589 , J:98866 )

• under mild lesioning conditions (right carotid ligation plus 40 min 10% O2), newborn homozygotes show attenuated hypoxia-ischemia induced CCL2 (chemokine (C-C motif) ligand 2; also, MCP-1) expression at 8 h post-hypoxia relative to wild-type; no genotype differences in CCL2 production are observed in animals undergoing longer periods of hypoxia-ischemia (severe insult) (J:69589)

• following right carotid artery ligation, newborn homozygotes (P9-P10) are resistant to moderate, but not to severe cerebral hypoxic-ischemic insults relative to wild-type mice (J:98866)

homeostasis/metabolism

decreased circulating interleukin-1 alpha level ( J:22964 )

• LPS-treated mice show a 5-fold decrease in IL-1alpha levels in vivo

decreased circulating interleukin-1 beta level ( J:22964 )

• in vivo, homozygous males injected with a high dose of LPS display undetectable levels of mature IL-1beta in their plasma; females are slightly less affected

decreased circulating interleukin-6 level ( J:22964 )

• after injection with a high dose of LPS, homozygotes display a moderate reduction in IL-6 levels relative to wild-type mice

decreased circulating tumor necrosis factor level ( J:22964 )

• after injection with a high dose of LPS, homozygotes display a moderate reduction in TNF levels relative to wild-type mice

decreased susceptibility to ischemic brain injury ( J:69589 , J:98866 )

• under mild lesioning conditions (right carotid ligation plus 40 min 10% O2), newborn homozygotes show attenuated hypoxia-ischemia induced CCL2 (chemokine (C-C motif) ligand 2; also, MCP-1) expression at 8 h post-hypoxia relative to wild-type; no genotype differences in CCL2 production are observed in animals undergoing longer periods of hypoxia-ischemia (severe insult) (J:69589)

• following right carotid artery ligation, newborn homozygotes (P9-P10) are resistant to moderate, but not to severe cerebral hypoxic-ischemic insults relative to wild-type mice (J:98866)

cardiovascular system

cardiovascular system phenotype ( J:107324 )

N • mice exhibit normal response to carotid ligation