Phenotypes associated with this allele

• Allele Symbol: Il6st^tm1Thir
• Allele Name: targeted mutation 1, Toshio Hirano
• Allele ID: MGI:2386991
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Il6st^tm1Thir/Il6st^tm1Thir	B6.Cg-Il6st^tm1Thir	MGI:3843778
hm2	Il6st^tm1Thir/Il6st^tm1Thir	involves: 129 * C57BL/6	MGI:3843817
hm3	Il6st^tm1Thir/Il6st^tm1Thir	Not Specified	MGI:3843660
cx4	Il6st^tm1Thir/Il6st^tm1Thir Tg(TcraH-Y,TcrbH-Y)71Vbo/?	involves: 129 * C57BL/6 * DBA	MGI:3843819
cx5	Il6st^tm1Thir/Il6st^tm1Thir Rag2^tm1Fwa/Rag2^tm1Fwa	involves: 129S/SvEv * C57BL/6	MGI:3843820

Genotype
MGI:3843778

hm1

• Allelic Composition: Il6st^tm1Thir/Il6st^tm1Thir
• Genetic Background: B6.Cg-Il6st^tm1Thir

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

skeleton

abnormal osteoblast physiology ( J:144906 )

• osteoblasts reduce their proliferation and their alkaline phosphatase activity by a greater amount than controls when cultured with IL-6 family cytokines

• proliferation reduction caused by IL-6/sIL-6R, IL-11, and LIF were 43%, 36%, and 13% compared to 32%, 20%, and 10% in controls

• osteoblast activity is increased 2.8- and 2.0- fold compared to controls when cultured with IL-6/sIL-6R or IL-11

abnormal bone structure ( J:144906 )

• skeleton area is 5% higher than in controls

increased bone mineral content ( J:144906 )

• bone mineral content is 16% higher than in controls

increased bone mineral density ( J:144906 )

• bone mineral density is 11% greater in these mice than in controls

increased trabecular bone thickness ( J:144906 )

• trabecular number and total bone volume of the tibia is increased by a third

• trabecular thickness is also increased and trabecular separation is decreased

increased bone mineralization ( J:144906 )

• mineral apposition rate is augmented in these mice

increased bone ossification ( J:144906 )

• bone formation rate is augmented in these mice

cellular

abnormal osteoblast physiology ( J:144906 )

• osteoblasts reduce their proliferation and their alkaline phosphatase activity by a greater amount than controls when cultured with IL-6 family cytokines

• proliferation reduction caused by IL-6/sIL-6R, IL-11, and LIF were 43%, 36%, and 13% compared to 32%, 20%, and 10% in controls

• osteoblast activity is increased 2.8- and 2.0- fold compared to controls when cultured with IL-6/sIL-6R or IL-11

Genotype
MGI:3843817

hm2

• Allelic Composition: Il6st^tm1Thir/Il6st^tm1Thir
• Genetic Background: involves: 129 * C57BL/6

skeleton

rheumatoid arthritis ( J:133059 )

• mice develop RA starting at 8 months of age

• incidence is about 45% between 11 and 15 months of age, and 100% in mice over 16 months of age

• RA includes swelling and redness of the paws and limited mobility of the ankle or wrist joints

• joints have severe synovitis with destructive changes including marked proliferation of the synovium, infiltration of inflammatory cells, fibrin deposits and severe bone destruction

• the elbows and knees are affected symmetrically in many diseased mice and become rigid

• severity scores are significantly higher in female mice than males (13.5 in year-old females versus 9.6 in year-old males)

osteoporosis ( J:133059 )

• osteoporosis is noted around inflamed joints of older mice

immune system

abnormal T cell clonal deletion ( J:133059 )

• injection with the T cell superantigen SEB does not cause clonal deletion of T-cells bearing Vbeta8 TCR chains as it does in wild-type mice

• inhibition of activation induced cell death by IL-6 is almost three times greater than in wild-type T cells

increased double-negative T cell number ( J:133059 )

• in older mice with arthritis, the frequency of double-negative thymocytes is increased by 40 fold

• this population included B cells, plasma cells and dendritic cells

decreased double-positive T cell number ( J:133059 )

• in older mice with arthritis, the frequency of double-positive thymocytes is reduced by 40 fold

• decreases in this population are observed starting at 18 weeks of age before arthritis as set in

increased neutrophil cell number ( J:133059 )

• increased numbers of neutrophils are found in the lymph nodes of mice with arthritis

increased activated T cell number ( J:133059 )

• almost all CD4⁺ T cells bear activation or memory markers

increased single-positive T cell number ( J:133059 )

• there is a three-fold increase in single-positive thymocytes of older mice with arthritis

• increases in this population are observed starting at 18 weeks of age before arthritis as set in

increased IgA level ( J:133059 )

• IgA levels are slightly elevated in mice one year of age

increased IgG1 level ( J:133059 )

• IgG1 levels are slightly elevated in mice one year of age

increased IgG2a level ( J:133059 )

• IgG2a levels are slightly elevated in female mice one year of age

increased IgG2b level ( J:133059 )

• IgG2b levels are slightly elevated in male mice one year of age

abnormal T cell activation ( J:133059 )

• T cells from lymph nodes of non-arthritic mice have higher rates of proliferation in response to anti-CD3 treatment than controls

abnormal thymocyte activation ( J:133059 )

• thymocytes from 12 week old mice hyper-proliferate in response to anti-CD3 treatment

increased autoantibody level ( J:133059 )

• 1 year old mice have elevated levels of rheumatoid factor (Ig class)

increased anti-nuclear antigen antibody level ( J:133059 )

• 1 year old mice have elevated levels of anti-ribonuclear protein antibodies with higher levels found in females

increased anti-double stranded DNA antibody level ( J:133059 )

• 1 year old mice have elevated levels of anti-dsDNA antibodies with higher levels found in females

increased anti-single stranded DNA antibody level ( J:133059 )

• 1 year old mice have elevated levels of anti-ssDNA antibodies with higher levels found in females

rheumatoid arthritis ( J:133059 )

• mice develop RA starting at 8 months of age

• incidence is about 45% between 11 and 15 months of age, and 100% in mice over 16 months of age

• RA includes swelling and redness of the paws and limited mobility of the ankle or wrist joints

• joints have severe synovitis with destructive changes including marked proliferation of the synovium, infiltration of inflammatory cells, fibrin deposits and severe bone destruction

• the elbows and knees are affected symmetrically in many diseased mice and become rigid

• severity scores are significantly higher in female mice than males (13.5 in year-old females versus 9.6 in year-old males)

hematopoietic system

abnormal T cell clonal deletion ( J:133059 )

• injection with the T cell superantigen SEB does not cause clonal deletion of T-cells bearing Vbeta8 TCR chains as it does in wild-type mice

• inhibition of activation induced cell death by IL-6 is almost three times greater than in wild-type T cells

increased double-negative T cell number ( J:133059 )

• in older mice with arthritis, the frequency of double-negative thymocytes is increased by 40 fold

• this population included B cells, plasma cells and dendritic cells

decreased double-positive T cell number ( J:133059 )

• in older mice with arthritis, the frequency of double-positive thymocytes is reduced by 40 fold

• decreases in this population are observed starting at 18 weeks of age before arthritis as set in

increased neutrophil cell number ( J:133059 )

• increased numbers of neutrophils are found in the lymph nodes of mice with arthritis

increased activated T cell number ( J:133059 )

• almost all CD4⁺ T cells bear activation or memory markers

increased single-positive T cell number ( J:133059 )

• there is a three-fold increase in single-positive thymocytes of older mice with arthritis

• increases in this population are observed starting at 18 weeks of age before arthritis as set in

increased IgA level ( J:133059 )

• IgA levels are slightly elevated in mice one year of age

increased IgG1 level ( J:133059 )

• IgG1 levels are slightly elevated in mice one year of age

increased IgG2a level ( J:133059 )

• IgG2a levels are slightly elevated in female mice one year of age

increased IgG2b level ( J:133059 )

• IgG2b levels are slightly elevated in male mice one year of age

abnormal T cell activation ( J:133059 )

• T cells from lymph nodes of non-arthritic mice have higher rates of proliferation in response to anti-CD3 treatment than controls

abnormal thymocyte activation ( J:133059 )

• thymocytes from 12 week old mice hyper-proliferate in response to anti-CD3 treatment

endocrine/exocrine glands

abnormal thymocyte activation ( J:133059 )

• thymocytes from 12 week old mice hyper-proliferate in response to anti-CD3 treatment

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
rheumatoid arthritis		DOID:7148	OMIM:180300	J:133059

Genotype
MGI:3843660

hm3

• Allelic Composition: Il6st^tm1Thir/Il6st^tm1Thir
• Genetic Background: Not Specified

growth/size/body

abnormal peritoneum morphology ( J:59922 )

• there is almost a 3-fold increase in the number of cells contained in the peritoneal exudate of 5-month old mice

spleen hyperplasia ( J:59922 )

• size of spleen increases with age with mean cellularity being over 2-fold higher than controls by 5 months of age

immune system

spleen hyperplasia ( J:59922 )

• size of spleen increases with age with mean cellularity being over 2-fold higher than controls by 5 months of age

increased B cell number ( J:59922 )

• the number of CD45R⁺ B cells is increased in in the enlarged lymph node organs

increased CD4-positive, alpha-beta T cell number ( J:59922 )

• the number of CD4-positive T cells increases by 1.3 to 2.7 fold in in the enlarged lymph node organs

increased CD8-positive, alpha-beta T cell number ( J:59922 )

• the number of CD8-positive T cells increases by 1.3 to 2.7 fold in the enlarged lymph node organs

abnormal B cell physiology ( J:59922 )

• B cells stimulated with anti-CD40 produce more immunoglobulins than controls

• addition of IL-6 to stimulation enhances even more the production of immunoglobulins

increased IgG2a level ( J:59922 )

• production of antigen-specific IgG2a is increased in these mice after immunization with T cell dependent antigen

increased IgG2b level ( J:59922 )

• production of antigen-specific IgG2b is increased in these mice after immunization with T cell dependent antigen

enlarged mesenteric lymph nodes ( J:59922 )

• by 5 months of age

lymph node hyperplasia ( J:59922 )

• by 5 months of age, enlargement occurs to cervical, axillar, inguinal, and mesenteric lymph nodes

enlarged axillary lymph nodes ( J:59922 )

• by 5 months of age

enlarged cervical lymph nodes ( J:59922 )

• by 5 months of age

enlarged inguinal lymph nodes ( J:59922 )

• by 5 months of age

abnormal dendritic cell antigen presentation ( J:113335 )

• bone marrow derived dendritic cells treated with IL-6 have a greater reduction in MHC-II surface expression than in controls

• dendritic cells isolated from lymph nodes have a 40% reduction in surface expression of MHC-II

increased interferon-gamma secretion ( J:59922 )

• activated T cells secrete 1.6-fold more IFN-gamma than controls

decreased interleukin-4 secretion ( J:59922 )

• CD4⁺ T cells produce less 0.6 fold-less IL-4 than controls when activated

hematopoietic system

spleen hyperplasia ( J:59922 )

• size of spleen increases with age with mean cellularity being over 2-fold higher than controls by 5 months of age

increased B cell number ( J:59922 )

• the number of CD45R⁺ B cells is increased in in the enlarged lymph node organs

increased CD4-positive, alpha-beta T cell number ( J:59922 )

• the number of CD4-positive T cells increases by 1.3 to 2.7 fold in in the enlarged lymph node organs

increased CD8-positive, alpha-beta T cell number ( J:59922 )

• the number of CD8-positive T cells increases by 1.3 to 2.7 fold in the enlarged lymph node organs

abnormal B cell physiology ( J:59922 )

• B cells stimulated with anti-CD40 produce more immunoglobulins than controls

• addition of IL-6 to stimulation enhances even more the production of immunoglobulins

increased IgG2a level ( J:59922 )

• production of antigen-specific IgG2a is increased in these mice after immunization with T cell dependent antigen

increased IgG2b level ( J:59922 )

• production of antigen-specific IgG2b is increased in these mice after immunization with T cell dependent antigen

nervous system

abnormal action potential ( J:130276 )

• the abnormal action potential of cardiomycoytes at 80% repolarization is not prolonged to the extent wild-type cardiomyocytes are when LIF is administered

abnormal channel response intensity ( J:130276 )

• L-type Ca²⁺ current intensities in cardiomyocytes are not influenced by IL-6 or LIF incubation as wild-type cardiomyocytes are

cardiovascular system

abnormal myocardial fiber physiology ( J:130276 )

• L-type Ca²⁺ current intensities in cardiomyocytes are not influenced by IL-6 or LIF incubation as wild-type cardiomyocytes are

• transient increases of intracellular calcium in cardiomyocytes are not influenced by IL-6 or LIF neither

Genotype
MGI:3843819

cx4

• Allelic Composition: Il6st^tm1Thir/Il6st^tm1Thir; Tg(TcraH-Y,TcrbH-Y)71Vbo/?
• Genetic Background: involves: 129 * C57BL/6 * DBA

immune system

abnormal negative T cell selection ( J:133059 )

• the number of CD8^lo single-positive thymocytes bearing transgenic TCR are several fold higher than in controls indicating a defect in negative selection

hematopoietic system

abnormal negative T cell selection ( J:133059 )

• the number of CD8^lo single-positive thymocytes bearing transgenic TCR are several fold higher than in controls indicating a defect in negative selection

Genotype
MGI:3843820

cx5

• Allelic Composition: Il6st^tm1Thir/Il6st^tm1Thir; Rag2^tm1Fwa/Rag2^tm1Fwa
• Genetic Background: involves: 129S/SvEv * C57BL/6

immune system

immune system phenotype ( J:133059 )

N • the arthritis observed in Il6st^tm1Thir homozygotes is not observed in these mice demonstrating functional lymphocytes are essential for disease