ABSTRACT
AIMS/HYPOTHESIS: For beta cells, contact with TNF-α triggers signalling cascades that converge on pathways important for cell survival and inflammation, specifically nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase pathways. Here, we investigated the function of baculoviral inhibitors of apoptosis repeat containing (BIRC) proteins in regulating TNF signalling cascades. METHODS: TNF regulation of Birc genes was studied by mRNA expression and promoter analysis. Birc gene control of cell signalling was studied in beta cell lines, and in islets from Birc2(-/-) and Birc3(-/-) mice, and from Birc3(-/-) Birc2Δ beta cell mice that selectively lack Birc2 and Birc3 (double knockout [DKO]). Islet function was tested by intraperitoneal glucose tolerance test and transplantation. RESULTS: TNF-α selectively induced Birc3 in beta cells, which in turn was sufficient to drive and potentiate NF-κB reporter activity. Conversely, Birc3(-/-) islets exhibited delayed TNF-α-induced IκBα degradation with reduced expression of Ccl2 and Cxcl10. DKO islets showed a further delay in IκBα degradation kinetics. Surprisingly, DKO islets exhibited stimulus-independent and TNF-dependent hyperexpression of TNF target genes A20 (also known as Tnfaip3), Icam1, Ccl2 and Cxcl10. DKO islets showed hyperphosphorylation of the JNK-substrate, c-Jun, while a JNK-antagonist prevented increases of Icam1, Ccl2 and Cxcl10 expression. Proteosome blockade of MIN6 cells phenocopied DKO islets. DKO islets showed more rapid loss of glucose homeostasis when challenged with the inflammatory insult of transplantation. CONCLUSIONS/INTERPRETATION: BIRC3 provides a feed-forward loop, which, with BIRC2, is required to moderate the normal speed of NF-κB activation. Paradoxically, BIRC2 and BIRC3 act as a molecular brake to rein in activation of the JNK signalling pathway. Thus BIRC2 and BIRC3 fine-tune NF-κB and JNK signalling to ensure transcriptional responses are appropriately matched to extracellular inputs. This control is critical for the beta cell's stress response.
Subject(s)
Inhibitor of Apoptosis Proteins/metabolism , Insulin-Secreting Cells/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Animals , Baculoviral IAP Repeat-Containing 3 Protein , Cell Line , Inhibitor of Apoptosis Proteins/genetics , Insulin-Secreting Cells/drug effects , JNK Mitogen-Activated Protein Kinases/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factor RelA/genetics , Transcription Factor RelA/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Ubiquitin-Protein LigasesABSTRACT
We measured serum osteocalcin levels in prepubertal children with human immunodeficiency virus (HIV) infection receiving highly active antiretroviral therapy including a protease inhibitor and uninfected control children. Osteocalcin values were significantly elevated in the HIV-infected patients. Though osteocalcin serves as an index of bone formation, it likely functions as a negative regulator of bone formation. Further study is necessary to determine whether protease inhibitors normalize bone physiology or decrease bone formation and reduce bone mineral density in children receiving these therapies.
Subject(s)
Antiretroviral Therapy, Highly Active , Bone and Bones/metabolism , HIV Infections/drug therapy , HIV Infections/metabolism , Osteocalcin/blood , Case-Control Studies , Child , Child, Preschool , Cross-Sectional Studies , Female , HIV Protease Inhibitors/therapeutic use , Humans , MaleABSTRACT
BACKGROUND: Ingestion is the principal route for food allergens, yet some highly sensitive patients may develop severe symptoms upon skin contact. CASE REPORT: We describe five cases of severe food allergic reactions through skin contact, including inhalation in one. METHODS: The cases were referred to a university allergy clinic, and evaluation comprised detailed medical history, physical examination, skin testing, serum total and specific IgE, and selected challenges. RESULTS: These cases were found to have a strong family history of allergy, early age of onset, very high total serum IgE level, and strong reactivity to foods by skin prick testing or RAST. Interestingly, reactions occurred while all five children were being breast-fed (exclusively in four and mixed in one). CONCLUSIONS: Severe food allergic reactions can occur from exposure to minute quantities of allergen by skin contact or inhalation. Food allergy by a noningestant route should be considered in patients with the above characteristics.
