Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains.
Interleukin (Il)-12 is a heterodimeric cytokine composed of 35 and 40 kD chains that plays a key role in the induction of Th1 cells, a T cell subset involved in many autoimmune diseases. We report here the cDNA sequence encoding the IL-12 p40 subunit from the autoimmune-prone non-obese diabetic (NOD) mouse, which spontaneously develops type 1 diabetes. Compared with the C57BL/6 sequence, there are two base changes that lead to amino acid replacements. Other autoimmune-prone strains, but not the diabetes-resistant NOR strain, share the same allele as NOD. We found both trans- and cis- allele-dependent effects on levels of basal and induced IL-12p40 expression. Furthermore, we show that one of these changes results in a structural change in the p40 molecule, as evidenced by the failure of a monoclonal antibody to bind NOD IL-12. These findings have implications for the predisposition to autoimmune responses in NOD and other autoimmune-prone mouse strains.
Ymer
S I
SI
The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050, Australia.
Huang
D
D
Penna
G
G
Gregori
S
S
Branson
K
K
Adorini
L
L
Morahan
G
G
D000818:Animals; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D018076:DNA, Complementary; D005786:Gene Expression Regulation; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D053762:Interleukin-12 Subunit p40; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D021122:Protein Subunits / Q000235:genetics* / Q000276:immunology; D016415:Sequence Alignment
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018664:Interleukin-12