IL10R1 loss-of-function alleles in rheumatoid arthritis and systemic lupus erythematosus.
OBJECTIVE
IL-10 is a pleiotropic cytokine involved in the regulation of innate and cell-mediated immunity and a key mediator within the disturbed SLE immune system. IL-10 binds to IL10R1, which is expressed on a variety of immune cells and activates the JAK-STAT pathway. Two (out of several known) genetic IL10R1 variants may alter IL-10 binding or signal transduction. Here we investigate the differential activity of these IL10R1 variants and their possible association with RA or SLE susceptibility.


METHODS
IL10R1-wt, IL10R1-S138G, IL10R1-G330R, or IL10R1- S138G +G330R were cloned into pIRESpuro3 and transfected into HeLa cells. Single cell clones were tested for IL-10-induced SOCS3- and SLAM gene expression by real-time PCR. DNA from 182 RA patients, 222 SLE patients, and 250 healthy controls was genotyped by allele-specific PCR.


RESULTS
A biphasic increase of SOCS3 mRNA was observed that peaked at 15 minutes and 4 hours after IL-10 stimulation. The presence of IL10R1 S138G and G330R showed a weaker induction of both SOCS3 and SLAM upon stimulation with IL-10. In RA a homozygous G330R genotype was more commonly present than in controls (15.4% vs. 7.6%; p<0.05). In SLE the G330R allele frequency was also increased (36.3% vs. 30.0%; p<0.05) without showing a gene-dose relationship at the genotype level.


CONCLUSIONS
Based on these results, both variants of the IL10R1 gene are loss-of-function alleles. IL10R1 G330R may possibly contribute to RA or SLE disease susceptibility in Caucasian populations.
Hermann
J
J
Department of Internal Medicine, Division of Rheumatology, Statistics and Documentation, Medical University of Graz, Medical University of Vienna, Austria.
Gruber
S
S
Neufeld
J B
JB
Grundtner
P
P
Graninger
M
M
Graninger
W B
WB
Berghold
A
A
Gasche
C
C
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D002999:Clone Cells; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D015703:Antigens, CD; C508609:IL10 protein, human; D011956:Receptors, Cell Surface; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1