Identification, isolation, and characterization of daintain (allograft inflammatory factor 1), a macrophage polypeptide with effects on insulin secretion and abundantly present in the pancreas of prediabetic BB rats

Abstract

A bioactive macrophage factor, the polypeptide daintain͞allograft inf lammatory factor 1 (AIF1), has been isolated from porcine intestine. It was discovered when searching for intestinal peptides with effects on insulin release, and its purification was monitored by the inf luence of the peptide fractions on pancreatic glucose-induced insulin secretion. Daintain͞AIF1 is a 146-aa residue polypeptide with a mass of 16,603 Da and an acetylated N terminus. An internal 44-residue segment with the sequence pattern -KR-KK-GKR-has a motif typical of peptide hormone precursors, i.e., dibasic sites for potential activation cleavages and at the sequentially last such site, the structure GKR. The latter is a signal for C-terminal amide formation in the processing of peptide hormones. Daintain͞AIF1 is immunohistochemically localized to microglial cells in the central nervous system and to dendritic cells and macrophages in several organs. A particularly dense accumulation of daintain͞AIF1-immunoreactive macrophages was observed in the insulitis affecting the pancreatic islets of prediabetic BB rats. When injected intravenously in mice, daintain͞AIF1 at 75 pmol͞kg inhibited glucose (1 g͞kg)-stimulated insulin secretion, with a concomitant impairment of the glucose elimination, whereas at higher doses (7.5 and 75 nmol͞kg), daintain͞AIF1 potentiated glucose-stimulated insulin secretion and enhanced the glucose elimination. Its dual inf luence on insulin secretion in vivo at different peptide concentrations, and the abundance of macrophages expressing daintain͞AIF1 in the pancreatic islets of prediabetic rats, suggest that daintain͞AIF1 may have a role in connection with the pathogenesis of insulin-dependent diabetes mellitus.

Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE−/− mice

“…AIF-1 is also called Iba1 (24), MRF-1 (microglia response factor-1) (25), and daintain (12). In addition, AIF-1 includes various splice variants (26).…”

“…Thus, AIF-1 may play a pivotal role not only in immune responses to alloantigens but also in various host responses to inflammatory stimuli. Furthermore, AIF-1 or AIF-1-like genes have been cloned from a wide range of organisms, from sponges to humans (10)(11)(12)(13). The nucleotide sequences in the sponge and vertebrates have 70% homology.…”

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

“…The AIF1 protein is involved in inflammatory responses, allograft rejection and macrophage regulation, 41 and has been implicated in T1D by functional studies, showing regulatory effects on insulin secretion in mice and accumulation in the pancreas of prediabetic Bio-Breeding (BB) rats. 42 Also, a number of studies have implicated this protein in other AIDs, 41 including a recent report showing that AIF1 may be crucial in the pathogenesis of rheumatoid arthritis. 43 In addition to rs2259571, we observed an independent association of rs3132451 in the promoter of the same gene, but this result was most likely an artifact, both judging from the heterogeneity within each of the two individual DRB1-DQA1-DQB1 haplotypes the associations mapped to and the negative result in the T1DGC families.…”

Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice

“…31 Groups of mice were immunized with or without ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], and the animals were subjected for MRM imaging to measure end diastolic volume, end systolic volume, SV, EF, and left ventricular wall thickness. Expectedly, both SV and EF were significantly reduced in immunized animals on different days as compared to healthy group [day 30 to 35: SV, 11.33 AE 2.17 mL versus 25.67 AE 4.67 mL; EF, 30.17 AE 2.52% versus 65.67 AE 0.88% (P < 0.05); and day 46: SV, 9.00 AE 2.52 mL versus 29.00 AE 0.58 mL; EF, 24.00 AE 4.51% versus 60.00 AE 1.15% (P < 0.01)].…”

“…One such model for cardiac autoimmunity is experimental autoimmune myocarditis (EAM), which involves induction of disease in susceptible rodent strains by immunizing animals with cardiac antigens or their peptide fragments. 23e25 In this study, we used the EAM model in A/J mice to demonstrate that ANT 1 possesses multiple immunodominant epitopes, and one of these, ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], was found to induce myocarditis in the immunized animals. Furthermore, myocarditogenicity of ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] was associated with the generation of T cells capable of producing predominantly IL-17A, and the antigen-sensitized T cells can transfer the disease to naïve recipients, suggesting that ANT 1 can be a potential autoantigen in the heart autoimmunity.…”