IL-4 inhibits the costimulatory activity of IL-2 or picolinic acid but not of lipopolysaccharide on IFN-gamma-treated macrophages.
We reported previously that IL-2 induces tumoricidal activity in IFN-gamma-treated murine macrophages. The present study was performed to investigate the regulation of IL-2-dependent tumoricidal activity in murine macrophage cell lines. The v-raf/v-myc-immortalized murine macrophage cell lines ANA-1, GG2EE, and HEN-CV did not express constitutive levels of cytotoxic activity against P815 mastocytoma cells. Moreover, these macrophage cell lines did not become tumoricidal after exposure to IL-4, IFN-gamma, IL-2 or LPS. However, these macrophages developed cytotoxic capabilities after incubation with either IFN-gamma plus IL-2 or IFN-gamma plus LPS. IL-4 inhibited IFN-gamma plus IL-2- but not IFN-gamma plus LPS-induced tumoricidal activity. This effect of IL-4 was not restricted to v-raf/v-myc-immortalized macrophage cell lines because similar results were obtained by using a macrophage cell line that was established from a spontaneous histiocytic sarcoma. The suppressive activity of IL-4 on the ANA-1 macrophage cell line was dose-dependent (approximately 12-200 U/ml) and was neutralized by the addition of anti-IL-4 mAb. IL-4 decreased the IFN-gamma-induced expression of mRNA for the p55 (alpha) subunit of the IL-2R in ANA-1 macrophages. Therefore, at least one mechanism by which IL-4 may have inhibited IFN-gamma plus IL-2-induced tumoricidal activity was by reducing macrophage IL-2R alpha mRNA expression. We have previously reported that picolinic acid, a tryptophan metabolite, is a costimulator of macrophage tumoricidal activity. We now report that IL-4 also inhibited IFN-gamma plus picolinic acid-induced cytotoxicity in ANA-1 macrophages. We propose that IL-2 and picolinic acid may have a common mechanism of action that is susceptible to IL-4 suppression.
Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick Cancer Research and Development Center, National Institutes of Health, MD 21702-1201.
G W
GW
Cox
U
U
Chattopadhyay
J J
JJ
Oppenheim
L
L
Varesio
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D004357:Drug Synergism; D015870:Gene Expression; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D010848:Picolinic Acids / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D015375:Receptors, Interleukin-2 / Q000235:genetics; D011994:Recombinant Proteins
D007376:Interleukin-2; D008070:Lipopolysaccharides; D010848:Picolinic Acids; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; C030614:picolinic acid