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Supplementary Table 1 (S1) | IL-1 family member knockout mouse phenotypes mouse
knockout mouse knockout
mouse knockout
mouse knockout
mouse knockout
mouse knockout
mouse knockout
mouse knockout
mouse knockout
mouse knockout
mouse knockout
human deficiency
human deficiency
IL-1α IL-1β IL-1α β IL-1Ra IL-18 IL-1R1 IL-1RAP IL-18Rα IL-18Rβ ST2 SIGIRR IL-1Ra APL unchallenged phenotype
normal1 normal1-3 normal1 retarded growth after weaning, lean body mass1, 4, 5
normal6 normal7, 8 normal9 normal10 normal11 normal12-14 normal15, 16 clinical features of rash, bone lesions, respiratory problems17,
18
X-linked non-syndromic mental retard-ation19, 20; autism21
response to cognate ligand
no in vitro or in vivo response to IL-17, 8, 22, 23
no in vitro or in vivo response to IL-1 or IL-339, 24-26
no in vitro or in vivo responses to IL-1810; defective NK IFNγ and cyto-toxicity10
no in vitro or in vivo responses to IL-1811
No in vivo response to IL-3327
response to challenge
decreased acute phase response and gene activation, no fever or anorexia after turpentine injection1,
3, 28; decreased lethality after zymosan challenge29
greater fever, more serum amyloid P after turpentine injection1, 30 enhanced neovascular-ization and expression of angiogenic factors after corneal injury31
less inflamm-atory cytokine production after IL-1β stimulation of mouse embryo fibroblasts32; more severe lung injury, lower survival after bleomycin33; increased frequency of preterm birth after LPS injection into uterus34
reduced acute phase response, no fever or anorexia after turpentine injection7, 22,
30, 35; no fever after leptin infusion36; no recruitment of leukocytes to brain after icv injection of IFNγ or TNF37; less severe emphysema after elastase challenge38
splenocytes, macro-phages, mouse embryo fibroblasts make increased inflamma-tory cytokines in response to multiple stimuli32, 39
increased responses in vitro and in vivo to IL-1 and to Toll-like receptor ligands15, 16,
40 more Th2 cytokines in vitro and in vivo in response to IL-3341
response to LPS
normal1-3 decreased survival5
decreased survival6; more resistant42
normal7, 8 normal11 Reduced tolerance to LPS challenge43
normal16; decreased survival15
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response to immunization (Abbreviation: EAE, experimental autoimmune encephalo-myelitis)
defective T cell pro-liferation, cytokine produc-tion, antibody response to T-dependent antigen44
defective T cell pro-liferation, cytokine production, antibody response to T-dependent antigen44
normal Th17 develop-ment during EAE45
normal primary and secondary antibody responses8
normal Th1 develop-ment in vitro but defective Th1 develop-ment in vivo after P. acnes10; defective Th17 develop-ment during EAE45
normal Th2 responses to Nippo-strongylus and in Ovalbumin-induced asthma model12, 14; defective primary Th2 responses to Shisoto-some13
contact hyper-sensitivity
defective contact hyper-sensitivity, defective trafficking of Langerhans cells to lymph node after contact sensitizer46
defective contact hyper-sensitivity, defective trafficking of Langerhans cells to lymph node after contact sensitizer2,
46
Delayed-Type Hyper-sensitivity (DTH)
poor T cell priming and defective DTH47
poor T cell priming and defective DTH47
enhanced DTH47
defective, reduced DTH7, 47
infectious disease
Candidi-asis: increased severity, greater lethality, lower Th1 response48; helminth infection: deficient Th2 response49
more tissue damage, pneumo-nia, bacterial growth, reduced survival after Strepto-coccus pneumo-niae infection50;
larger granulomas after Myco-bacterium tuberculosis (H37Rv) infection54; larger lesions, more bacterial growth after cutaneous Staphylo-coccus
decreased susceptibility to Listeria monocyto-genes5; enhanced granulomas in liver, more Th2 cytokines, more liver damage after Propioni-bacterium
increased resistance to Listeria mono-cytogenes56; less IFNγ and delayed viral clearance after influenza infection57; less IFNγ after murine cyto-
increased susceptibility to Listeria mono-cytogenes7; no change in susceptibility to Listeria mono-cytogenes 8; larger granulomas, more neutrophils, more
Normal host defense against Myco-bacterium infection62; suscepti-bility to infection with Trypano-soma gondii63
more inflam-mation, reduced survival in Candida or Aspergillus infections64; greater inflam-mation and lethality after Myco-bacterium tuberculosis
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larger lesions, more bacterial growth after cutaneous Staphylo-coccus aureus infection51; greater lethality after influenza infection52; greater viral load, lower survival in herpes simplex virus infection53; candidiasis leads to increased severity, greater lethality, lower Th1 response48; helminth infection: deficient Th2 response49
aureus infection51; candidiasis: increased severity, greater lethality, lower Th1 response48
acnes infection55
megalovirus infection58; increased suscepti-bility to Leishmania59
bacteria, more lethality after Myco-bacterium tuberculosis infection (Kurono strain but not H37Rv strain)60; greater incidence, lower survival in Strepto-coccus pneumoniae meningitis61; less lung pathology, worse survival during influenza infection52; no recruitment of leukocytes to brain during Trypanosoma brucei infection37
infection65
arthritis decreased
severity of chronic destructive arthritis induced by Strepto-coccus pyogenes cell wall injection66,
67
less bone loss, no cartilage loss in TNF transgene-driven arthritis68
spontaneous arthritis on Balb/c background1
reduced incidence and severity in CIA69
Experimental Autoimmune Encephalo-
slower onset, decreased
enhanced susceptibility to EAE70
resistant to EAE71 sensitive to
lower incidence, severity of
resistant to EAE45
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myelitis (EAE) severity of EAE70
EAE45 EAE, fewer Th17 cells72, 73
Systemic Lupus Erythematosis
less severe disease in lupus model74
more severe disease in lupus model40
IBD increased
incidence and frequency of necrotizing entero-colitis75; more severe disease induced by dextran sulfate76
more severe colitis, greater mortality after Citrobacter infection77
greater severity in dextran sulfate colitis16, 78
asthma reduced
severity in Ovalbumin-induced asthma model79
reduced severity in Ovalbumin-induced asthma model79
reduced severity in Ovalbumin-induced asthma model79
increased severity in short-term Ovalbumin-induced asthma model79
reduced severity in chronic Ovalbumin-induced asthma model80
reduced severity in mild (but not in severe) Ovalbumin-induced asthma model and in occupational allergen asthma model81, 82; reduced eosinophil trafficking in Ovalbumin-induced asthma model55; less airway remodeling upon repeated inhalation of LPS83
Transfer of ST2-deficient T cells exacerbates Ovalbumin-induced inflam-mation84; reduced airway inflam-mation and alternatively activated macrophage function in Ovalbumin-asthma model85
increased severity in Ovalbumin-asthma model41
transplant knockout
islets transplanted into wildtype
knockout islets transplanted into wildtype
enhanced allograft rejection86
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host have prolonged survival39
host have more rapid rejection39
skin psoriasis-like
skin inflam-mation on Balb/c background87
defective Langerhans cell migration out of skin in response to antigen88; protection from dermatitis on caspase 1-transgenic back-ground89; protection from atopic dermatitis induced by Staphylo-coccus aureus90
less skin inflam-mation, acute phase response upon phorbol ester painting91; delayed epidermal permeability barrier development during develop-ment92
fibrosis impaired
wound healing, more inflam-mation, scarring after wounding93
reduced inflam-mation, remodeling, fibrosis in bleomycin model94; reduced fibrosis, scarring in wounds95; reduced fibrosis after liver injury96; protection from cardiac fibrosis in experimental autoimmune myocarditis97
lung protection
against inflam-mation, matrix breakdown, emphysema
protection against inflam-mation, matrix breakdown, emphysema
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after long-term exposure to cigarette smoke98
after long-term exposure to cigarette smoke99
renal decreased
severity in glomerulo-nephritis model100
decreased severity in glomerulo-nephritis model101
Athero-sclerosis & cardiovascular
reduced athero-sclerotic lesion size102 higher total choles-terol, non-HDL choles-terol on athero-genic diet102
reduced athero-sclerotic lesion size102, 103
greater foam cell lesion area, lower serum non-HDL cholesterol on cholesterol/cholate diet104; massive aortic inflam-mation and destruction but no athero-sclerosis on ApoE back-ground105; spontaneous arteritis on Balb/c back-ground106; enhanced neo-intima formation after vessel injury107
reduced athero-sclerotic lesion size108
reduced athero-sclerotic lesion size109,
110; lower blood pressure with high fat diet109; less neo-intima formation after coronary artery ligation111; no autoimmune myocarditis after immuni-zation with cardiac myosin peptide112
no cardiac hypertrophy after pressure overload113
Reduced survival following surgically-induced aortic pressure overload114
stroke & ischemia-reperfusion
decrease in infarct size after cerebral ischemia model115
modest decrease in lesion size, lower neuro-pathology score in cerebral hypoxia-ischemia model116
reduced infarct size, neuronal degeneration in cerebral ischemia model117; reduced liver damage after ischemia-reper-
more inflam-mation and renal failure in renal ischemia model40
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fusion118 Neurodegener-ation
greater neuronal inflam-mation, damage, mortality after infusion of amyloid Aβ 1-42 peptide into brain119
increased neuronal damage, delayed recovery in excito-toxicity model120, 121; lower microglial activation after stress122
no febrile seizures123; delayed time to seizures after injection of bicuculline methio-dide124; decreased inflammation following penetrating brain injury117
increased neuronal degeneration after LPS injection into brain in knockout of AcPb splice form24
delayed recovery from kainate-induced ataxia121
lipids and obesity
resistant to developing obesity on high-fat diet; decreased food intake, greater energy expenditure, lower lipid accumu-lation4, 125, 126
Hyper-phagic, obese, insulin resis-tant127, 128
slower onset of diabetes on NOD back-ground129; obesity and insulin resistance in older mice130; less insulin resistance on high-fat diet131
obese, insulin resistant127
pain reduced
sensitivity to inflam-matory and neuropathic but not post-operative pain132
decreased basal pain sensitivity to temperature or mechanical stimulus133; decreased neuropathic pain after nerve injury134; reduced post-operative pain135
decreased basal pain sensitivity to temperature or mechanical stimulus133
cancer reduced
growth and metastasis
poor tumori-genesis in
impaired growth of implanted
enhanced tumori-genesis in
increased tumori-genesis in
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of implanted wildtype tumors in IL-1α knockout host35; no rejection136 or enhanced rejection137 of implanted IL-1α knockout tumors in wild-type host
methylcholanthrene model137; poor or no growth of implanted IL-1β knockout tumors in wildtype host136
IL-1αβ knockout tumors in wildtype host136
methylchol-anthrene model137
colon carcino-genesis model78
other impaired
fertilization by IL-1ra KO sperm138
reduced severity in acute pancreatitis model139; reduced anxiety behavior98; impaired hippocampal memory (spatial memory, fear condi-tioning)140
Increased suscepti-bility to strepto-zotocin-induced diabetes141
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