In vitro effects of Type I interferons (IFN tau and IFN alpha) on bovine hepatocytes cultured with or without Kupffer cells

In cattle, maternal recognition of early pregnancy depends on the effects of the embryonic signal interferon (IFN)-τ. IFN-stimulated genes have been upregulated in the maternal liver during early pregnancy. In this study, primary hepatocyte cell culture models were evaluated for their suitability to test Type I IFN effects invitro. The expression of target genes (interferon-stimulated gene 15 (ISG-15), interferon-induced GTP-binding protein (MX-1), C-X-C motif chemokine 10 (CXCL-10), CXCL-5, insulin-like growth factor 1 (IGF-1), IGF binding protein 2 (IGFBP-2)) was measured using reverse transcription-quantitative polymerase chain reaction in hepatocytes from monoculture or in indirect coculture with Kupffer cells (HKCid) on Days 1, 2, 3 and 4 of culture (n=21 donor cows). Gene expression was also measured on Day 4 after challenging the cultures with recombinant IFNτ, IFNα, progesterone (P4), IFNτ+IFNα or IFNτ+P4 for 6h. A significant increase in the mRNA expression of target genes in hepatocytes was shown in response to stimulation with IFNτ. The Kupffer cells in coculture did not influence the effects of IFNτ in hepatocytes. In conclusion, primary bovine hepatocyte cultures are suitable for stimulation experiments with Type I IFNs and as an extrauterine model for embryo-maternal communication. The proposed endocrine action of IFNτ in the liver may affect maternal metabolism and immune function in the liver

Intra-amniotic LPS modulates expression of antimicrobial peptides in the fetal sheep lung

BACKGROUND: Damage-associated molecular patterns (DAMPs) and antimicrobial peptides (AMPs) are components of pulmonary innate immunity and tissue repair. We hypothesized that DAMPs and AMPs would increase in response to fetal pulmonary inflammation caused by chorioamnionitis in a time-dependent manner. METHODS: Fetal sheep were exposed to intra-amniotic saline or LPS (10mg) between 5 hours and 15 days prior to preterm delivery at 125±2 days. Lung tissue mRNAs for pro-inflammatory cytokines; AMPs: myeloid antimicrobial peptide-29 (MAP29), dodecapeptide, sheep beta-defensin-1 (SBD1), sheep beta-defensin-2 (SBD2); DAMPs: IL-1α, lactoferrin, heat-shock protein-70 (HSP70), high-mobility group box protein-B1 (HMGB1), receptor for advanced glycation endproducts (RAGE) were measured by RT-qPCR. Immunohistochemistry of DAMPs and in situ hybridization of AMPs was performed. RESULTS: IL-1α, IL-1β, IL-6, IL-8, IL-10, MCP-1, and TNF-α mRNA increased after LPS exposure. MAP29, dodecapeptide, SBD1 and SBD2 mRNA were suppressed at 24 hours. MAP29 and dodecapeptide mRNA then increased at 8 days. Lactoferrin increased at 24 hours. There were no changes for HMGB1, HSP70 or RAGE. MAP29 and dodecapeptide localized to alveolar cells, increased 8 days after exposure to LPS. CONCLUSION: AMPs are initially suppressed in the fetal lung by LPS-induced chorioamnionitis. The late induction of MAP29 and Dodecapeptide may be related to lung repair

Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis

Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (T-FH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by T-FH cells, preventing proper spatial organization of T-FH cells to form T-FH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption. Moderate consumption of alcohol is associated with protection from some autoimmune diseases. Here the authors show that ethanol and its metabolite acetate can protect mice from collagen-induced arthritis and provide evidence that the mechanism of this effect might be via inhibition of the effector function of T follicular helper cells