Effects of IL-12 on in vivo cytokine gene expression and Ig isotype selection.
The effects of murine rIL-12 on cytokine gene expression and Ig secretion were studied in vivo. In untreated mice IL-12 enhanced IFN-gamma and IL-10 gene expression and protein secretion, reduced base line IL-3 and IL-4 gene expression, and increased serum IgG2a concentration. In mice that had been injected with goat anti-mouse IgD antibody (G alpha M delta) to induce increases in IL-3, IL-4, and IL-10 gene expression and serum IgE, IgG1, IgG2a, and IgG3 concentrations, the simultaneous injection of IL-12 enhanced IFN-gamma and IL-10 gene expression and suppressed IL-3 and IL-4 gene expression and serum IgG and IgE responses. Anti-IFN-gamma mAb neutralized most, but not all, IFN-gamma produced by mice treated with G alpha M delta and IL-12. Anti-IFN-gamma mAb enhanced IL-3 and IL-4 gene expression, did not affect IL-10 or IFN-gamma gene expression, and increased serum IgG1, IgG2a, and IgG3 levels, but had relatively little effect on serum IgE in these mice. In contrast to its effects in G alpha M delta-treated mice, IL-12 failed to inhibit the IgE response to G alpha M epsilon antibody, which stimulates mIgE+ B cells to secrete IgE. These observations demonstrate that: 1) IL-12 may limit its own effects by inducing the production of a cytokine (IL-10) that down-regulates both IL-12 production and IL-12-induced IFN-gamma production; 2) IL-12 inhibits the production of at least one cytokine, IL-3, that is not generally regarded to be strictly Th1- or Th2-associated; 3) IL-12 inhibits switching to IgE secretion to a greater extent than it inhibits switching to other Ig isotypes; and 4) the in vivo effects of IL-12 are, to a large extent, IFN-gamma-dependent.
Morris
S C
SC
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Madden
K B
KB
Adamovicz
J J
JJ
Gause
W C
WC
Hubbard
B R
BR
Gately
M K
MK
Finkelman
F D
FD
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D016207:Cytokines / Q000235:genetics*; D005260:Female; D007072:Immunoglobulin D / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000378:metabolism*; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12; D007377:Interleukin-3 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D007378:Interleukins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011947:Receptors, Antigen, B-Cell / Q000276:immunology
D016207:Cytokines; D007072:Immunoglobulin D; D007132:Immunoglobulin Isotypes; D007377:Interleukin-3; D007378:Interleukins; D009838:Oligodeoxyribonucleotides; D011947:Receptors, Antigen, B-Cell; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma