Positive regulatory role of IL-12 in macrophages and modulation by IFN-gamma.
Similar to myeloid dendritic cells, murine macrophages and macrophage cell lines were found to express a surface receptor for IL-12. As a result, peritoneal macrophages could be primed by IL-12 to present an otherwise poorly immunogenic tumor peptide in vivo. Using binding analysis and RNase protection assay, we detected a single class of high affinity IL-12 binding sites (K(d) of approximately 35 pM) whose number per cell was increased by IFN-gamma via up-regulation of receptor subunit expression. Autocrine production of IL-12 was suggested to be a major effect of IL-12 on macrophages when the cytokine was tested alone or after priming with IFN-gamma in vitro. In vivo, combined treatment of macrophages with IFN-gamma and IL-12 resulted in synergistic effects on tumor peptide presentation. Therefore, our findings suggest a general and critical role of IL-12 in potentiating the accessory function of myeloid APC.
Grohmann
U
U
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Belladonna
M L
ML
Vacca
Carmine
C
Bianchi
R
R
Fallarino
F
F
Orabona
C
C
Fioretti
M C
MC
Puccetti
P
P
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D007371:Interferon-gamma / Q000008:administration & dosage / Q000502:physiology*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009842:Oligopeptides; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; C494087:Stat3 protein, mouse; C494091:Stat4 protein, mouse; D015534:Trans-Activators; C076546:tumor rejection antigen P815A, mouse; D018664:Interleukin-12; D007371:Interferon-gamma