Induction of dissociated cytokine profiles by ISRAA with selective critical involvement of ERK1/2 in its signaling functions.
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.
Department of Molecular Medicine, Princess Al‑Jawhara Center for Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
Sahar
S
Elhannan
Department of Molecular Medicine, Princess Al‑Jawhara Center for Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
Safa
S
Taha
Department of Molecular Medicine, Princess Al‑Jawhara Center for Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
Noureddine
N
Ben Khalaf
Department of Molecular Medicine, Princess Al‑Jawhara Center for Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
Halla
H
Bakheit
Biotechnology Program, College of Graduate Studies, Arabian Gulf University, Manama, Bahrain.
M Dahmani
MD
Fathallah
Department of Molecular Medicine, Princess Al‑Jawhara Center for Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
Moiz
M
Bakhiet
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism
D002070:Butadienes; D016207:Cytokines; D004791:Enzyme Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D007093:Imidazoles; D008222:Lymphokines; D009570:Nitriles; D011725:Pyridines; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C113580:U 0126; C540855:immune system released activating agent, mouse; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093642:SB 203580