Mouse Genome Informatics
hm1
    Il6tm1Poli/Il6tm1Poli
CAnNCrl.129S(Cg)-Il6tm1Poli
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• male homozygotes display decreased sensitivity to the depressing effects of LPS and IL-1beta on sickness behavior, with attenuated social exploration, immobility and body weight loss relative to wild-type males
• in response to i.p. injection of IL-1beta (1.0 g/mouse) and LPS (2.5 g/mouse), male homozygotes exhibit a shorter duration of immobility relative to wild-type males
• in response to i.p. injection of IL-1beta (1.0 g/mouse) and LPS (2.5 g/mouse), male homozygotes show an attenuated reduction in social interaction relative to wild-type males
• notably, i.c.v. administration of IL-1beta and LPS depresses social exploration only in wild-type mice, whereas mutants remain unaffected

growth/size/body
• in response to i.p. injection of IL-1beta (1.0 g/mouse) and LPS (2.5 g/mouse), male homozygotes show an attenuated body weight loss relative to wild-type males

tumorigenesis
• in response to i.p. injection with pristane oil, homozygotes exhibit delayed and reduced ascite development, fail to display changes in the cellular content of ascitic fluids, and do not develop any clinically or histologically detectable plasmacytomas
• occasional mature plasma cells with atypical or anaplastic features are detected in the ascitic fluid and mesenteric tissues of some homozygotes, indicating initial plasma cell transformation

immune system
• 8- to 10-week-old male homozygotes are less affected by peripheral and central injections of IL-1beta and LPS than wild-type male littermates
• pristane-treated homozygotes exhibit a reduced frequency of B cell differentiation and plasma cell formation, with rare morphological signs of activation and scant B-cell blast aggregates
• in response to i.p. injection with pristane oil, homozygotes show an attenuated inflammatory response, with reduced peritoneal granuloma formation, reduced histiocyte and fibroblast number in granulomatous tissue, and only rare signs of B cell activation

hematopoietic system
• pristane-treated homozygotes exhibit a reduced frequency of B cell differentiation and plasma cell formation, with rare morphological signs of activation and scant B-cell blast aggregates


Mouse Genome Informatics
hm2
    Il6tm1Poli/Il6tm1Poli
involves: 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• at 24 hrs or longer after partial hepatectomy, homozygotes exhibit significantly increased mortality and morbidity (40%) relative to wild-type (10%) or IL-6-treated homozygotes (8%) (J:37026)
• in contrast, male and female homozygotes show no significant changes in survival relative to wild-type counterparts during CLP-induced sepsis (J:48865)

liver/biliary system
• homozygotes exhibit normal liver architecture prior to partial (70%) hepatectomy
• however, at 4 to 5 days after 70% hepatectomy, livers of jaundiced homozygotes appear small and erythematous with extensive areas of necrosis
• at 36 to 72 hrs after partial hepatectomy, livers of most homozygotes show massive hepatic necrosis and ballooning degeneration of hepatocytes, in the absence of apoptosis
• little or no necrosis is observed in the livers of the 50% of homozygotes that survive 96 and 120 hrs after hepatectomy
• after partial hepatectomy, homozygotes display impaired liver regeneration typified by liver necrosis and failure
• hepatectomized homozygotes show decreased levels of induced hepatocyte DNA synthesis, with 20-25% of wild-type levels at 36 hrs and >48 hours after surgery
• treatment with a single preoperative dose of IL-6 restores hepatocyte proliferation to nearly wild-type levels and prevents liver damage
• between 24 and 96 hrs after partial hepatectomy, ~28% of homozygotes exhibit lethargy, anorexia, and tremulousness, some with gross jaundice
• in contrast, no hepatic necrosis or signs of liver failure are noted in hepatectomized wild-type or IL-6-treated homozygotes at any time after hepatectomy

homeostasis/metabolism
• during sepsis induced by cecal ligation and puncture (CLP), male homozygotes maintain a profound hypothermia but fail exhibit subsequent fever
• homozygotes subjected to resuscitated HS exhibit less lung injury, (i.e. reduced pneumocyte swelling, interstitial edema, and cellular infiltration) relative to sham controls
• in addition, homozygotes subjected to resuscitated HS fail to exhibit significant focal liver necrosis relative to sham controls

growth/size/body
N
• male homozygotes show a normal cachectic response during sepsis induced by cecal ligation and puncture (CLP) (J:48865)

behavior/neurological
• male homozygotes display prolonged anorexia during sepsis

immune system
• homozygotes subjected to resuscitated hemorrhagic shock (HS) fail to exhibit significant infiltration of PMN into the lung interstitium and alveoli relative to sham controls
• in addition, homozygotes subjected to resuscitated HS fail to exhibit significant liver PMN infiltration relative to sham controls
• homozygotes subjected to resuscitated HS fail to exhibit features of postresuscitation inflammation, concomittant with impaired liver STAT3 and NF-kappaB activation

hematopoietic system
• homozygotes subjected to resuscitated hemorrhagic shock (HS) fail to exhibit significant infiltration of PMN into the lung interstitium and alveoli relative to sham controls
• in addition, homozygotes subjected to resuscitated HS fail to exhibit significant liver PMN infiltration relative to sham controls


Mouse Genome Informatics
hm3
    Il6tm1Poli/Il6tm1Poli
involves: 129S/SvEv * MF1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Il6tm1Poli/Il6tm1Poli mice exhibit increased susceptibility to Candida albicans infection

mortality/aging
N
• homozygotes are viable, fertile and developmentally normal relative to wild-type mice (J:17249)

immune system
N
• homozygotes show normal distribution of T cell subpopulations and % of activated T cells relative to wild-type mice (J:17249)
• homozygotes do not exhibit enhanced mortality upon exposure to mouse hepatitis virus under non-pathogen-free conditions (J:17249)
• uninfected homozygotes show a significant decrease in total IgA fecal content; similarly, intragastrically-infected homozygotes exhibit significantly lower Candida-specific fecal IgA levels relative to wild-type mice
• uninfected homozygotes display normal IgE production; however, after i.v. infection with C. albicans (PCA-2), homozygotes show reduced Candida-specific IgE levels relative to wild-type mice
• uninfected homozygotes display normal IgG2a production; however, after i.v. infection with C. albicans (PCA-2), homozygotes show increased Candida-specific IgG2a levels relative to wild-type mice
• in response to systemic challenge with a live vaccine strain of C. albicans, homozygotes fail to mount Th1-associated protective immunity and develop a T cell reactivity biased towards the Th2 pathway
• in response to a low virulence C. albicans strain that normally induces Th1-mediated immunity in wild-type mice, infected homozygotes default to a Th2 response which can be redirected to the Th1 phenotype by IL-10 neutralization
• non-ovariectomized homozygotes show normal osteoclastogenesis and osteoclast bone-resorbing activity, as shown by normal osteoclast surface and normal number of osteoclast precursors (CFU-GM) in the bone marrow
• however, unlike ovariectomized wild-type mice, homozygotes fail to exhibit increased numbers of CFU-GM in the bone marrow following estrogen depletion
• after systemic or intragastric infection with C. albicans, homozygotes exhibit a greater increase in circulating IL-10 levels relative to wild-type mice
• notably, IL-10 neutralization increases Th1-mediated resistance in homozygotes with systemic candidiasis
Candidai-infected homozygotes exhibit reduced serum IL-12 levels relative to infected wild-type mice
• in contrast, serum IL-4 levels remain unaffected during candidiasis
• homozygotes show increased susceptibility to either systemic or intragastric infection with virulent C. albicans relative to wild-type mice
• systemically infected homozygotes display increased fungal loads in the liver, kidney and brain
• intragastrically infected homozygotes show increased fungal growth in the stomach and esophagus, and increased yeast dissemination in the kidney, but are able to clear the mucosal infection as efficiently as wild-type mice
• notably, C. albicans-infected homozygotes do not develop as severe renal pathology in the cortex as the otherwise resistant wild-type mice

skeleton
• non-ovariectomized homozygotes display significantly reduced cortical bone volume relative to wild-type mice
• non-ovariectomized homozygotes exhibit normal trabecular bone structure and volume relative to wild-type mice
• however, unlike ovariectomized wild-type mice, homozygotes fail to exhibit a 50% loss in trabecular bone volume following estrogen depletion
• non-ovariectomized female homozygotes exhibit higher rates of bone turnover, despite normal trabecular volume
• unlike ovariectomized wild-type mice, homozygotes fail to exhibit a 50% bone loss or a 3- to 5-fold increase in indices of bone turnover and bone resorption following estrogen depletion
• non-ovariectomized homozygotes show normal osteoclastogenesis and osteoclast bone-resorbing activity, as shown by normal osteoclast surface and normal number of osteoclast precursors (CFU-GM) in the bone marrow
• however, unlike ovariectomized wild-type mice, homozygotes fail to exhibit increased numbers of CFU-GM in the bone marrow following estrogen depletion

homeostasis/metabolism
N
• homozygotes exhibit normal circadian variations in body temperature relative to wild-type mice (J:30643)
• after systemic or intragastric infection with C. albicans, homozygotes exhibit a greater increase in circulating IL-10 levels relative to wild-type mice
• notably, IL-10 neutralization increases Th1-mediated resistance in homozygotes with systemic candidiasis
Candidai-infected homozygotes exhibit reduced serum IL-12 levels relative to infected wild-type mice
• in contrast, serum IL-4 levels remain unaffected during candidiasis
• homozygotes fail to exhibit a febrile response to LPS (50 g/kg i.p) or recombinant murine (rm) IL-1beta (10 g/kg i.p or higher)
• homozygotes exhibit a small, atypical slow-onset fever response to a combination of i.p. injection of LPS plus recombinant human (rh) IL-6
• importantly, homozygotes display a rapid and long-lasting fever response to injection of rhIL-6 (500 ng/mouse i.c.v), but fail to exhibit a febrile response to rmIL-1beta (100 ng/mouse i.c.v)
• male homozygotes exhibit reduced levels of dopamine in the hypothalamus
• striatal levels of HVA, the major metabolite of dopamine, are increased, suggesting a higher turnover for this neurotransmitter in the mutant striatum

behavior/neurological
N
• 4-month-old homozygous males show a normal response to scopolamine-induced hypermotility relative to age-matched wild-type males (J:95923)
• relative to wild-type males, mutant males exhibit a faster development of tolerance to the analgesic effect of morphine, indicating a modified opioid system
• male homozygotes display increased intermale aggression, already evident on the first encounter; by the 5th encounter, ~80% of mutant males become dominant whereas wild-type males divide themselves equally in dominants and subordinates (~50%)
• specifically, male homozygotes show a shorter latency to the first attack, an increased number of attacks, more chasing, less freezing, and a higher number and longer duration of offensive postures
• young and adult male homozygotes exhibit increased cognitive performance associated with a significant reduction in hippocampal choline acetyltransferase activity
• under basal conditions, 4-month-old homozygous males show no increase in the step-through latency relative to wild-type males
• however, 4-month-old male homozygotes show a decreased response to scopolamine-induced amnesia
• in the radial maze task, both young and adult male homozygotes display a better and faster acquisition, in terms of a reduced number of errors and days to reach the criterion, relative to age-matched wild-type males
• notably, 12 month-old homozygotes exhibit a faster acquisition (22 days vs 30 days to reach the criterion), with a robust tendency to enter an adjacent arm that is apparently lost in age-matched wild-type mice
• male homozygotes fail to exhibit an analgesic response to a physical restraint stress
• male homozygotes show no significant differences in the magnitude of basal nociceptive responses to a thermal stimulus
• however, male homozygotes exhibit a reduced analgesic response to the administration of low (1.25 mg/kg) but not high (2.5 mg/kg) doses of morphine
• in accord with a reduced opioid response, male homozygotes show a relevant reduction of mu opioid receptors in the midbrain, but not in the hypothalamus
• male homozygotes tend to show reduced levels of affiliative behaviors, as shown by decreased rates of anogenital, nose or body sniffing relative to wild-type males

nervous system
• male homozygotes exhibit reduced levels of dopamine in the hypothalamus
• striatal levels of HVA, the major metabolite of dopamine, are increased, suggesting a higher turnover for this neurotransmitter in the mutant striatum

hematopoietic system
• uninfected homozygotes show a significant decrease in total IgA fecal content; similarly, intragastrically-infected homozygotes exhibit significantly lower Candida-specific fecal IgA levels relative to wild-type mice
• uninfected homozygotes display normal IgE production; however, after i.v. infection with C. albicans (PCA-2), homozygotes show reduced Candida-specific IgE levels relative to wild-type mice
• uninfected homozygotes display normal IgG2a production; however, after i.v. infection with C. albicans (PCA-2), homozygotes show increased Candida-specific IgG2a levels relative to wild-type mice
• in response to systemic challenge with a live vaccine strain of C. albicans, homozygotes fail to mount Th1-associated protective immunity and develop a T cell reactivity biased towards the Th2 pathway
• in response to a low virulence C. albicans strain that normally induces Th1-mediated immunity in wild-type mice, infected homozygotes default to a Th2 response which can be redirected to the Th1 phenotype by IL-10 neutralization
• non-ovariectomized homozygotes show normal osteoclastogenesis and osteoclast bone-resorbing activity, as shown by normal osteoclast surface and normal number of osteoclast precursors (CFU-GM) in the bone marrow
• however, unlike ovariectomized wild-type mice, homozygotes fail to exhibit increased numbers of CFU-GM in the bone marrow following estrogen depletion

integument
• male homozygotes fail to exhibit an analgesic response to a physical restraint stress
• male homozygotes show no significant differences in the magnitude of basal nociceptive responses to a thermal stimulus
• however, male homozygotes exhibit a reduced analgesic response to the administration of low (1.25 mg/kg) but not high (2.5 mg/kg) doses of morphine
• in accord with a reduced opioid response, male homozygotes show a relevant reduction of mu opioid receptors in the midbrain, but not in the hypothalamus


Mouse Genome Informatics
cx4
    Cebpbtm1Vpo/Cebpbtm1Vpo
Il6tm1Poli/Il6tm1Poli

involves: 129S/SvEv * MF1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
N
• double homozygotes exhibit no major histologic abnormalities in the lymph nodes and spleen or signs of severe plasmacytosis in the lymph nodes (J:35883)
• although B cell development is delayed, neither spleen hyperplasia nor abnormal expansion of the lymphoid or myeloid compartments is observed, suggesting that Il6 inactivation prevents the pathological development of Castleman's disease observed in Cebpbtm1Vpo mice (J:35883)