Interleukin-4 mediates down regulation of antiviral cytokine expression and cytotoxic T-lymphocyte responses and exacerbates vaccinia virus infection in vivo.
Interleukin-4 (IL-4) promotes the growth of Th2-type cells while down regulating the development of Th1-type cells. It has been suggested that the actions of this factor inhibit Th1-type effector activity in vivo and may underlie the development of diseases normally controlled by cell-mediated immune responses. Here, we show that clearance of recombinant vaccinia viruses (VV) engineered to express the gene for murine IL-4 is markedly delayed in mice compared with control recombinant VV. While antiviral antibody levels and NK activity in mice given control virus or IL-4-expressing virus were similar, antiviral cytotoxic T-lymphocyte responses were profoundly suppressed throughout the course of infection with the latter. Limiting dilution analysis of IL-4-virus-infected spleens revealed a marked reduction in numbers of cytotoxic T-lymphocyte precursors. Furthermore, reverse transcriptase PCR analysis of splenic mRNA prepared from mice infected with the IL-4-expressing VV showed a marked down regulation of IL-12, gamma interferon, and IL-2 gene expression compared with that from mice given control virus. IL-4 also inhibited the production of nitric oxide (NO), a potent mediator of antimicrobial activity. Together, these data show that IL-4 markedly suppresses the development of antiviral cell-mediated immune responses in vivo with deleterious effects on virus clearance.
Sharma
D P
DP
Viral Engineering and Cytokine Research Group, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Ramsay
A J
AJ
Maguire
D J
DJ
Rolph
M S
MS
Ramshaw
I A
IA
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004274:DNA, Recombinant; D004279:DNA, Viral; D015536:Down-Regulation; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008808:Mice, Inbred CBA; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014615:Vaccinia / Q000235:genetics / Q000276:immunology*; D014616:Vaccinia virus
D016207:Cytokines; D004274:DNA, Recombinant; D004279:DNA, Viral; D015847:Interleukin-4