Comparative effects of heme and metalloporphyrins on interferon-gamma-mediated pathways in monocytic cells (THP-1)

Previous results have demonstrated links between cell-mediated immunity, interferon (IFN)-gamma and neopterin production with heme, porphyrins, and iron metabolism. In this study, we compared the effects of heme, several metalloporphyrins, protoporphyrin IX, and iron on the signal or IFN-gamma-mediated pathways, such as the expression of major histocompatibility complex class II antigens, neopterin formation, and the degradation of tryptophan. Using the human monocytic cell line, THP-1, we found that heme, Zn-mesoporphyrin, Zn-deuteroporphyrin, Co-protoporphyrin, and iron reduced the efficiency of the IFN-gamma signal. In addition, Zn-mesoporphyrin almost fully inhibited IFN-gamma-induced degradation of tryptophan by the heme protein, indoleamine 2,3-dioxygenase. In contrast, tin-protoporphyrin enhanced the IFN-gamma effects as seen by increased neopterin production, enhanced tryptophan degradation, and elevated HLA-DR antigen expression on cells. These effects are considered to be due to the action of heme, metalloporphyrins, iron, or heme byproducts on the IFN-gamma signal, rather than to direct effects on IFN-gamma-induced enzymatic pathways. Heme and metalloporphyrins were previously shown to affect heme oxygenase activity, T cell growth, and lipid peroxidation and to modulate interleukin 2 activity. These pathways are also known to be influenced by IFN-gamma, and our data suggest that heme and metalloporphyrins may directly modulate the efficiency of the IFN-gamma signal.