Role of beta1 and beta2 subunits of the interleukin-12 receptor in determining T helper 1/T helper 2 responses in vivo in the rat.
Interleukin-12 (IL-12) responsiveness, and hence capacity to mount a T helper type 1(Th1) immune response, may be regulated via differential expression of the IL-12 receptor beta2 subunit at least in vitro in human and murine cells. To test whether a similar phenomenon operates in vivo in the rat we cloned and sequenced partial cDNAs for rat IL-12Rbeta1 and IL-12Rbeta2 subunits and analysed expression of these genes in vivo in two rat strains with different Th1/Th2 bias. After treatment with mercuric chloride (HgCl2), Brown-Norway rats develop Th2-biased autoimmunity whereas Lewis rats do not develop autoimmunity, instead becoming resistant to Th1-biased diseases to which they are normally susceptible. We report close sequence homology between the segments of the rat IL-12R genes sequenced and corresponding mouse genes (95.6% and 92% for IL-12Rbeta1 and IL-12Rbeta2, respectively). Both Brown-Norway and Lewis rats express both beta1 and beta2 subunits of IL-12 receptor in vivo in spleen; Brown-Norway rats express the beta2 subunit at a lower level than Lewis rats. After HgCl2 treatment, IL-12Rbeta1 expression was not altered but there was down-regulation of IL-12Rbeta2 expression in both strains. We conclude that relative under-expression of IL-12Rbeta2 by Brown-Norway rats contributes to their Th2 bias, and that down-regulation of IL-12Rbeta2 after HgCl2 administration in Lewis rats underlies subsequent resistance to induction of Th1-biased diseases.
Gillespie
K M
KM
Academic Renal Unit, and *Diabetes and Metabolism Unit, University of Bristol, Southmead Hospital, Bristol, UK.
Szeto
C C
CC
Betin
V M
VM
Mathieson
P W
PW
D000818:Animals; D015551:Autoimmunity; D001483:Base Sequence; D015870:Gene Expression; D018664:Interleukin-12 / Q000378:metabolism*; D008627:Mercuric Chloride / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D018123:Receptors, Interleukin / Q000235:genetics*; D053707:Receptors, Interleukin-12; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D013154:Spleen / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
C508438:IL12RB1 protein, human; C508439:IL12RB2 protein, human; C508440:Il12rb1 protein, mouse; C508442:Il12rb1 protein, rat; C508443:Il12rb2 protein, mouse; C508444:Il12rb2 protein, rat; D020033:Protein Isoforms; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D008627:Mercuric Chloride