Induction of dissociated cytokine profiles by ISRAA with selective critical involvement of ERK1/2 in its signaling functions

Abstract

Abstract. The immune system-released activating agent (ISRAA) is an immune mediator activated as a result of a nerve stimulus initiated by immune challenge. We have previously demonstrated that ISRAA and tumor necrosis factor (TNF) receptor 1 (TNFR1) share an interspecies-conserved motif (72% homology) that induces the apoptosis and proliferation of human peripheral blood mononuclear cells (hPBMCs) in a dose-dependent manner. In the present study, cytokine profiles were examined in response to the stimulation of hPBMCs with ISRAA. Furthermore, the signaling pathways induced by ISRAA were mapped. The results revealed high measurable levels of TNF-α, interleukin (IL)-6, IL-8, IL-10 and interferon (IFN)-γ, but not IL-4, IL-17 (IL-17A) or transforming growth factor (TGF)-β. The analysis of signaling pathways revealed the activation of extracellular-regulated protein kinase (ERK)1/2 as a downstream signal in the mitogen-activated protein kinase (MAPK) pathway during TNF-α and IL-6 production and apoptosis, but not during proliferation following stimulation with ISRAA by triggering the Fas-associated protein with death domain (FADD). STAT3 was found to be unphosphorylated in the ISRAA-stimulated hPBMCs, and STAT3 was ubiquitously expressed in unstimulated cells, suggesting that ISRAA has a protein inhibitor of activated STAT (PIAS)-like activity, by functioning as a negative regulator of the effects of STAT3 on the Janus kinase (JAK)/STAT pathway. The determination of the nature of cytokine responses together with the signaling pathways of cellular activity induced by ISRAA paves the way for the investigation of a potential target of ISRAA and for the development of novel therapeutic approaches for the treatment of immune-regulated disorders.

A role for the immune system-released activating agent (ISRAA) in the ontogenetic development of brain astrocytes

“…Thus, ISRAA is considered to be a novel T-cell signalling molecule, induced by the nervous system (2). In biological assays, ISRAA illustrates dose-dependent biological activities, as low doses of 50pg/ml result in cell activation, while high doses of 5 μg cause apoptosis (3, 4). Analysis of green fluorescent protein (GFP) expression highlights that ISRAA is transcribed and expressed in lymphoid organs.…”

A role for the immune system-released activating agent (ISRAA) in the ontogenetic development of brain astrocytes

“…Thus, ISRAA is considered to be a novel T-cell signalling molecule, induced by the nervous system [2]. In biological assays, ISRAA illustrates dose-dependent biological activities, as low doses of 50pg/ml result in cell activation, while high doses of 5μg cause apoptosis [3,4]. Analysis of green fluorescent protein (GFP) expression highlights that ISRAA is transcribed and expressed in lymphoid organs.…”