Interleukin-1 down-regulates gene and surface expression of interleukin-1 receptor type I by destabilizing its mRNA whereas interleukin-2 increases its expression.
The interleukin-1 receptor type I (IL-1RtI) plays an important role in the biological effects of IL-1, but regulation of its surface and gene expression remains unknown. We found that occupancy of 2-15% of the IL-1 surface receptor results in dramatic down-regulation of IL-1RtI both at the mRNA and cell surface level in murine D10S cells, a subline of T-helper type 2 cells. At these low occupancy levels (3 x 10(-12) to 3 x 10(-13) M), the reduction in IL-1RtI surface expression appears at 24 hr and continues to 48 and 72 hr. At the mRNA level, low occupancy of the IL-1R results in decreased IL-1RtI mRNA stability; steady state half-life of the IL-1RtI mRNA is reduced from 6 to 1 hr after exposure to 3 x 10(-12) M IL-1. This down-regulation of IL-1RtI by IL-1 is blocked by cycloheximide, suggesting de novo protein synthesis is necessary for decreased RNA stability. Low concentrations of human IL-1 beta, murine and rabbit IL-1 alpha or beta similarly down-regulated IL-1RtI, whereas low concentrations of human IL-1 alpha failed to reduce the receptor surface expression, despite inducing a full proliferative response. We also observed that the effect of IL-1 on this down-regulation was not through protein kinase C (PKC), since PMA rapidly increased IL-1RtI mRNA levels within 30 min and persisted for 24 hr. IL-2 up-regulated IL-1RtI in D10S cells at both mRNA and protein levels. These results demonstrate that low occupancy of IL-1 receptors induces down-regulation of IL-1RtI surface as well as mRNA expression. The regulation of IL-1RtI gene expression may be one of the mechanisms by which IL-1-mediated events are controlled.
Ye
K
K
Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts.
Koch
K C
KC
Clark
B D
BD
Dinarello
C A
CA
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology*; D006207:Half-Life; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D051379:Mice; D011493:Protein Kinase C / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000032:analysis* / Q000235:genetics*; D017472:Receptors, Interleukin-1
D007375:Interleukin-1; D007376:Interleukin-2; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011493:Protein Kinase C