IL-28A is a key regulator of T-cell-mediated liver injury via the T-box transcription factor T-bet.
OBJECTIVE
T-cell-mediated fulminant hepatitis is a potentially life-threatening event for which the underlying pathogenic mechanisms are not fully understood. Here, we demonstrate a key regulatory role of IL-28A in T-cell-mediated hepatitis.


METHODS
We cloned the murine IL-28A gene by reverse-transcription polymerase chain reaction, assessed the effects of recombinant IL-28A, and generated IL-28A-transgenic mice.


RESULTS
IL-28A induced TH1 cytokine production by CD4+ T lymphocytes in a T-bet-dependent manner and was up-regulated in a murine model of T-cell-mediated hepatitis upon Con A administration. In vivo, CD4+ T cells from newly created IL-28A-transgenic animals revealed an increased proliferation and proinflammatory TH1 cytokine production, as compared with wild-type mice. In addition, IL-28A-transgenic mice showed markedly augmented Con A-induced hepatitis with up-regulated interferon-gamma cytokine production, as compared with wild-type mice. Transgenic mice exhibited an up-regulation of the interferon-gamma-T-bet signaling pathway in Con A hepatitis, and augmented hepatitis in these mice was suppressed by crossing them with T-bet-deficient mice. In addition, in vivo blockade of interferon-gamma but not IL-4 suppressed augmented liver inflammation in transgenic mice, suggesting that IL-28A induces the T-bet signaling pathway in T-cell-induced hepatitis. Finally, IL-28A-specific antisense phosphorothioate oligonucleotides suppressed liver pathology in Con A-treated wild-type mice, as compared with the case of control oligonucleotides.


CONCLUSIONS
IL-28A emerges as a key regulatory cytokine with pathogenic function in T-cell-mediated liver injury. Thus, targeting of IL-28A represents a potential novel approach for therapy of Th1-mediated inflammatory diseases such as T-cell-mediated hepatitis.
Siebler
Juergen
J
Laboratory of Immunology, I. Medical Clinic, University of Mainz, Lasngenbeckstrasse 1, 55131 Mainz, Germany.
Wirtz
Stefan
S
Weigmann
Benno
B
Atreya
Imke
I
Schmitt
Edgar
E
Kreft
Andreas
A
Galle
Peter R
PR
Neurath
Markus F
MF
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D003001:Cloning, Molecular; D018387:Codon, Initiator; D003208:Concanavalin A; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D017114:Liver Failure, Acute / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008934:Mitogens; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000098815:T-bet Transcription Factor
D000906:Antibodies; D018387:Codon, Initiator; D007376:Interleukin-2; D007378:Interleukins; D008934:Mitogens; D016376:Oligonucleotides, Antisense; D018121:Receptors, Cytokine; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C471046:interleukin 28alpha receptor; D003208:Concanavalin A; D015847:Interleukin-4; D007371:Interferon-gamma