Interleukin 2 regulation of mitogen induction of immune interferon (IFN gamma) in spleen cells and thymocytes

Interleukin 2 (IL 2) or T-cell growth factor induced the production of immune interferon (IFN_γ) in C57B1/6 mouse spleen cell cultures, and enhanced mitogen-induced IFN_γ production in both spleen cells and thymocytes. Staphylococcal enterotoxin A, but not phytohemagglutinin P (PHA-P), induced IFN_γ production in thymocytes. IL 2 enhanced this production by almost 12-fold, while having no effect on the negative response to PHA-P. The IFN activity was shown to be IFN_γ by neutralization with specific antiserum. A strict correlation between IL 2 induction or enhancement of IFN_γ production and cell proliferation was not observed, probably indicating that non-IFN-producing cells also proliferated in the presence of IL 2. The data indicate that IL 2 can both induce IFN_γ and modulate mitogen induction of IFN_γ.     

Expression of transfected human interferon-gamma DNA: evidence for cell-specific regulation

The production of interferon-gamma (IFN-gamma) has been limited to two specific cell types of the immune system, T cells and large granular lymphocytes. Interleukin 2 (IL 2) appears to be the primary physiologic stimulus for IFN-gamma production in vitro, but other agents, such as antigens, phorbol myristic acetate, concanavalin A, or other plant lectins, may also act as effective inducing agents for IFN-gamma production. Little is known, however, as to the role, if any, that genetic factors may play in the induction process. We now report that, on stable transfection of the genomic human IFN-gamma 8.6 Kb BamH DNA fragment into a mouse T lymphoblast cell line, both mRNA expression and synthesis of human IFN-gamma were stimulated by both the physiologic ligand IL 2 and phorbol ester. In contrast, we have been unable to induce with extracellular stimulants IFN-gamma production or cytoplasmic mRNA after introduction of this gene into NIH 3T3 fibroblasts, thus suggesting that the extracellular regulation of the expression of IFN-gamma may be controlled by a developmental mechanism(s) intrinsic for cells of lymphoid lineage.     

1,25-Dihydroxycholecalciferol-induced differentiation of myelomonocytic leukemic cells unresponsive to colony stimulating factors and phorbol esters

The murine myelomonocytic leukemia cell line WEHI-3B D+, which differentiates in response to granulocyte colony stimulating factor (G-CSF), can also be induced to differentiate into monocyte-macrophages by phorbol myristate acetate (PMA) treatment, whereas the WEHI-3B D- subline, which is unresponsive to G-CSF and PMA, can be induced to differentiate to granulocytes as well as monocytes by 1,25-dihydroxycholecalciferol [1,25-(OH)2 D3], the biologically active metabolite of vitamin D3. A newly developed variant of the WEHI-3B D+ line, named WEHI-3B D+ G, which was responsive to G-CSF but not to PMA, was also differentiated to granulocytes by 1,25-(OH)2 D3. Although vitamin D3 has been reported to induce macrophage differentiation in responsive tumor cells, this is the first demonstration that 1,25-(OH)2 D3 can induce granulocyte differentiation. In both differentiation pathways, cessation of cellular proliferation accompanies changes in morphologic and cytochemical properties of the cells. This suggests that leukemic cell lines unresponsive to differentiation agents acting at the cell surface retain their ability to differentiate in response to agents that do not act via the plasma membrane such as 1,25-(OH)2 D3, which has cytosolic/nuclear receptors. Vitamin D3 could act through different cellular pathways inducing differentiation or by bypassing only the first step of a common differentiation cascade used by agents with cell surface receptors such as CSF. These results suggest that low doses of 1,25-(OH)2 D3 may be useful in combination with hemopoietic growth factors (CSFs) as therapeutic agent to induce leukemic cell differentiation in vivo.     

Antimicrobial resistance in humans,livestock and the wider environment

Antimicrobial resistance (AMR) in humans is inter-linked with AMR in other populations, especially farm animals, and in the wider environment. The relatively few bacterial species that cause disease in humans, and are the targets of antibiotic treatment, constitute a tiny subset of the overall diversity of bacteria that includes the gut microbiota and vast numbers in the soil. However, resistance can pass between these different populations; and homologous resistance genes have been found in pathogens, normal flora and soil bacteria. Farm animals are an important component of this complex system: they are exposed to enormous quantities of antibiotics (despite attempts at reduction) and act as another reservoir of resistance genes. Whole genome sequencing is revealing and beginning to quantify the two-way traffic of AMR bacteria between the farm and the clinic. Surveillance of bacterial disease, drug usage and resistance in livestock is still relatively poor, though improving, but achieving better antimicrobial stewardship on the farm is challenging: antibiotics are an integral part of industrial agriculture and there are very few alternatives. Human production and use of antibiotics either on the farm or in the clinic is but a recent addition to the natural and ancient process of antibiotic production and resistance evolution that occurs on a global scale in the soil. Viewed in this way, AMR is somewhat analogous to climate change, and that suggests that an intergovernmental panel, akin to the Intergovernmental Panel on Climate Change, could be an appropriate vehicle to actively address the problem.