Modulation of the IL-12/IFN-gamma axis by IFN-alpha therapy for hepatitis C.
Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.
Byrnes
Adriana A
AA
Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Li
Ding-You
DY
Park
Kiwon
K
Thompson
Douglas
D
Mocilnikar
Cathleen
C
Mohan
Parvathi
P
Molleston
Jean P
JP
Narkewicz
Michael
M
Zhou
Huanfang
H
Wolf
Stanley F
SF
Schwarz
Kathleen B
KB
Karp
Christopher L
CL
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000627:therapeutic use; D016899:Interferon-beta / Q000008:administration & dosage / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D010865:Pilot Projects; D013329:Structure-Activity Relationship
D016898:Interferon-alpha; D018664:Interleukin-12; D016899:Interferon-beta; D007371:Interferon-gamma