Expression of IL-10 in Th memory lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3.
In Th1 and Th2 memory lymphocytes, the genes for the cytokines interleukin (IL)-4 and interferon-gamma (IFN-gamma) are imprinted for expression upon restimulation. This cytokine memory is based on expression of the transcription factors T-bet for IFN-gamma, and GATA-3 for IL-4, and epigenetic modification of the cytokine genes. In Th2 cells, expression of the cytokine IL-10 is also induced by GATA-3. Here, we show that this induction is initially not accompanied by epigenetic modification of the IL-10 gene. Only after repeated restimulation of a memory Th2 cell in the presence of IL-4, extensive histone acetylation of the IL-10 gene is detectable. This epigenetic imprinting correlates with the development of a memory for IL-10 in repeatedly restimulated Th2 cells. In Th1 cells, IL-10 expression is induced by IL-12, but the IL-10 gene lacks detectable histone acetylation. Accordingly, IL-10 expression in restimulated memory Th1 cells remains conditional on the presence of IL-12. This finding defines a potential anti-inflammatory role for IL-12 in Th1 recall responses. While in primary Th1 responses IL-12 is required to induce expression of the pro-inflammatory cytokine IFN-gamma, in secondary Th1 responses IFN-gamma re-expression is independent of IL-12, which still is able to induce expression of the anti-inflammatory cytokine IL-10.
Chang
Hyun-Dong
HD
Deutsches Rheumaforschungszentrum Berlin, Berlin, Germany.
Helbig
Christina
C
Tykocinski
Lars
L
Kreher
Stephan
S
Koeck
Juliana
J
Niesner
Uwe
U
Radbruch
Andreas
A
D000818:Animals; D002478:Cells, Cultured; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018392:Genomic Imprinting / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4