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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

© 2010 Macmillan Publishers Limited. All rights reserved.



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




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




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




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




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




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




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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