Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements.
The cytoplasmic domain of the receptor for interleukin 10 (IL-10R) contains two box 3 sequence motifs that have been identified in the signal-transducing receptor subunits for IL-6-type cytokines and noted to be required for activating STAT3 and inducing transcription through IL-6-responsive elements. To determine whether the IL-10R has signaling functions similar to IL-6R in cells normally expressing these receptors, leukocytes of the B-, T-, and NK-cell lineages were treated with either cytokine. Both cytokines activated factors that bound to the sis-inducible element and included STAT1 and STAT3. The cell response to IL-10 characteristically differed from that to IL-2/IL-15, IL-4, and interferon gamma. The signaling capabilities of the IL-10R for activating specific STAT proteins and inducing gene transcription were defined by reconstitution of receptor functions in transfected tissue culture cells. COS-1 cells, co-expressing the human IL-10R and individual STAT proteins, confirmed a preference of the IL-10R for STAT3 and STAT1. Unlike many hematopoietin receptors, the IL-10R did not detectably activate STAT5. The IL-10R, together with reporter gene constructs containing different IL-6-responsive gene elements, reconstituted in hepatoma cells an induction of transcription by IL-10 that was comparable to that by IL-6. This regulation could not be appreciably modified by enhanced expression of STAT proteins. The similar actions of IL-10R and IL-6R on the induction of endogenous IL-6-responsive genes were demonstrated in hepatoma cells stably expressing the IL-10R. These receptor functions required the presence of the box 3 motifs, as shown by the analysis of the mouse IL-10R constructs containing progressively truncated cytoplasmic domains. The data demonstrate that the IL-10R, unlike other members of the interferon receptor family, is highly effective in recruiting the signaling pathways of IL-6-type cytokine receptors.
Lai
C F
CF
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Ripperger
J
J
Morella
K K
KK
Jurlander
J
J
Hawley
T S
TS
Carson
W E
WE
Kordula
T
T
Caligiuri
M A
MA
Hawley
R G
RG
Fey
G H
GH
Baumann
H
H
D000209:Acute-Phase Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology; D007962:Leukocytes / Q000378:metabolism; D008113:Liver Neoplasms; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000502:physiology*; D053701:Receptors, Interleukin-10; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10