title: An interspecies conserved motif of the mouse immune system-released activating agent (ISRAA) induces proliferative effects on human cells.
abstract: We have recently described an immune system-released activating agent (ISRAA) as a nervous system-induced factor that stimulates immune responses in the mouse spleen. However, the human ISRAA has not yet been identified. In this study, we examined the effects of the mouse ISRAA protein on human peripheral blood mononuclear cells (PBMCs), to observe if the biological activity of this molecule is consistent between the two different species. Mouse ISRAA demonstrated dose-dependent dualistic effects on human cells, as 5 µg exhibited positive apoptosis and 50 pg exhibited significant proliferation (P<0.05). Furthermore, immunosuppressed cells from patients undergoing immunosuppressive therapy demonstrated significant proliferation to 50 pg ISRAA (P<0.05). Studies to compare sequences in different species revealed a preserved motif, exhibiting 72% similarity with the interspecies conserved signal peptide motif of tumor necrosis factor receptor 1 (TNFR1). A mutant ISRAA lacking this motif was produced and tested for its biological effects. The mutant ISRAA demonstrated neither apoptotic nor proliferative effects compared with wild type. Therefore, an interspecies conserved domain of ISRAA constitutes the active site of the molecule, and its effects on immunocompromised cells should be investigated for future therapies in the treatment of immunosuppressive disorders.
authors.affiliation: Department of Molecular Medicine, Princess Al-Jawhara Center for Genetics and Inherited Diseases, Arabian Gulf University, Manama 26671, Bahrain.
authors.forename: Safa
authors.initials: S
authors.lastname: Taha
authors.affiliation: Biotechnology Program, College of Graduate Studies, Arabian Gulf University, Manama 26671, Bahrain.
authors.forename: Mohamed Dahmani
authors.initials: MD
authors.lastname: Fathallah
authors.affiliation: Department of Molecular Medicine, Princess Al-Jawhara Center for Genetics and Inherited Diseases, Arabian Gulf University, Manama 26671, Bahrain.
authors.forename: Moiz
authors.initials: M
authors.lastname: Bakhiet
mesh_terms: D000293:Adolescent; D000328:Adult; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D016415:Sequence Alignment; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D055815:Young Adult
chemical_list: D008222:Lymphokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C540855:immune system released activating agent, mouse