Femtograms of Interferon-γ Suffice to Modulate the Behavior of Jurkat Cells: A New Light in Immunomodulation

Abstract

Since interferon-γ (IFN-γ) tunes both innate and adaptive immune systems, it was expected to enter clinical practice as an immunomodulatory drug. However, the use of IFN-γ has been limited by its dose-dependent side effects. Low-dose medicine, which is emerging as a novel strategy to treat diseases, might circumvent this restriction. Several clinical studies have proved the efficacy of therapies with a low dose of cytokines subjected to kinetic activation, while no in vitro data are available. To fill this gap, we investigated whether low concentrations, in the femtogram range, of kinetically activated IFN-γ modulate the behavior of Jurkat cells, a widely used experimental model that has importantly contributed to the present knowledge about T cell signaling. In parallel, IFN-γ in the nanogram range was used and shown to activate Signal transducer and activator of transcription (STAT)-1 and then to induce suppressor of cytokine signaling-1 (SOCS-1), which inhibits downstream signaling. When added together, femtograms of IFN-γ interfere with the transduction cascade activated by nanograms of IFN-γ by prolonging the activation of STAT-1 through the downregulation of SOCS-1. We conclude that femtograms of IFN-γ exert an immunomodulatory action in Jurkat cells.

Analysis of Emission Infrared Spectra of Protein Solutions in Low Concentrations

“…In this paper, the developed method was used for the study of water protein solutions (interferon-gamma (IFNγ), antibodies to interferon-gamma (Ab to IFNγ)) and glycine buffer (GB) at low concentration. The issue of sensitivity when dealing with low concentrations is of utmost importance, in particular, given the fact that some studies [2][3][4][5][6][7] have revealed the effects observed in protein solutions at low concentrations that can hardly be explained directly by the properties of protein and the solvent, i.e., water. Furthermore, the present study analyzed the properties of the protein (IFNγ) dissolved in the above-mentioned solutions at low concentration.…”

The different effect of pharmacological or low-doses of IFN-γ in endothelial cells are mediated by different intracellular signaling pathways

“…Concerning IFN-γ, low-doses of SKA IFN-γ potentiated the activity of natural killer cells isolated from patients with early-stage colon cancer 28 . In Jurkat cells, low-dose SKA IFN-γ exerted an immunomodulatory action by tuning signal transduction and gene expression 18 .…”

“…10 ng/ml of vascular endothelial growth factor (VEGF) (PeproTech London UK) were used as positive control. The cells were stained with crystal violet to visualize the width of the wound and images were captured with a 4X objective using a phase contrast microscope 18 . The wound area was calculated by ImageJ software and expressed using an arbitrary value scale.…”

“…It should also be recalled that, in spite of its enormous therapeutic potential in immune diseases and in cancer, the use of IFN-γ is limited by its dose-dependent side effects 17 . We have previously shown that very low-doses of IFN-γ exert an immunomodulatory action in Jurkat cells 18 . Here we compare the effects of different concentrations of IFN-γ on the behavior of human EC, the first cells exposed to circulating IFN-γ.…”

Regulation of Inflammatory Reaction in Health and Disease

“…Of fundamental importance in understanding the mechanisms of regulation of inflammatory response was the model of the immune balance, that is, the reciprocal relationships between some lymphocyte subpopulations, T-helper 1 (Th1), Th2, regulatory T cells (T-reg) and Th17. Preclinical and clinical studies on the use of multicomponent/multitarget drugs [ 32 , 33 , 34 , 35 , 36 , 37 ] and physiological low dose cytokines [ 38 , 39 , 40 , 41 , 42 , 43 ] have opened new scenarios on the possibilities of treating acute and chronic inflammatory diseases (also on an autoimmune basis).…”