Inhibition of mouse mast cell proliferation and proinflammatory mediator release by benzodiazepines.

Mast cell (MC) activation may occur in vitro and in vivo following stimulation with various immunologic or nonimmunologic agents. Such activation leads to the release of several biological mediators, including vasoactive amines, nitric oxide and cytokines, which account for the adverse effects observed during allergic reactions. While high affinity binding sites for benzodiazepines (BZDs) have been reported on MC, the effects of the ligation of these receptors on the proliferation of, and the mediator release from, these cells are poorly documented. In the present work, we have examined the effects of midazolam and of diazepam on the proliferation of mucosal (MMC)-like and of serosal (CTMC)-like mouse MC. In addition, we have studied the effects of these BZDs on beta-hexosaminidase, TNF-alpha and nitrite release induced from mouse mast cells through IgE receptor activation. We demonstrated that each of the two BZDs studied inhibited the proliferation of MMC- and CTMC-like elements in a dose-dependent fashion (10 to 100 microM). Furthermore, the BZDs inhibited the IgE-mediated release of beta-hexosaminidase, TNF-alpha and nitrites from MMC- or CTMC-like cells. Altogether, these data provide new insights into the pharmacological regulation of MC activation and may lead to the discovery of new and potent antiallergic compounds.

Phagocytic and tumor necrosis factor alpha response of human mast cells following exposure to gram-negative and gram-positive bacteria.

Recent studies have implicated rodent mast cells in the innate immune response to infectious bacteria. We report that cord blood-derived human mast cells (CBHMC) obtained from culture of cord blood progenitors phagocytozed and killed various gram-negative and gram-positive bacteria and simultaneously released considerable amounts of tumor necrosis factor alpha. Overall, the extent of the endocytic and exocytic response of CBHMC correlated with the number of adherent bacteria. Thus, human mast cells are intrinsically capable of mediating microbial recognition and of actively contributing to the host defense against bacteria.

Investigation of the effects of 50 Hz magnetic fields on purified human hematopoietic progenitors.

Epidemiological reports suggest a possible association between exposure to extremely low frequency electromagnetic fields (ELF-EMFs) and the frequency of leukemia in men working in the field of electricity or in children living near power lines. At present, there is no experimental evidence for such an association. In this study we investigated the effects of 50 Hz EMFs (sinusoidal EMF of 10 microT or 1 mT) on human purified hematopoietic progenitor cells which are the first targets of a leukemogenic process. The results failed to reveal any significant changes in cell proliferation, cell kinetics, ultrastructure or clonogenic potential of these progenitors which could be related to a leukemogenic effect.

Effects of 50 Hz magnetic fields on C-myc transcript levels in nonsynchronized and synchronized human cells.

The effects of 50 Hz electromagnetic fields (EMFs) on the expression of the c-myc oncogene, known to be involved in normal cell proliferation and possibly also in tumor processes, were investigated in nonsynchronized human lymphoid cells immortalized by Epstein-Barr virus. Viral injury to such cells makes them a good model for exploring the possible cancer-promoting effects of 50 Hz magnetic fields. Parallel experiments were conducted on human HL60 leukemic cells. Cells were exposed to sinusoidal 50 Hz EMFs at 10 microT or 1 mT for 20 min, 1 h, 24 h, or 72 h. Exposure was performed either immediately after refeeding or 1.5 h after refeeding. C-myc transcript values were assessed by Northern blot analysis and normalized to those of the noninducible gene GaPDH. No statistically significant difference between the c-myc transcript levels of control and exposed cells was found in lymphoid or leukemic cells under our experimental conditions, either after short exposures of 20 min and 1 h or after longer exposures of 24 and 72 h. Other experiments were carried out with pseudosynchronized cells in an attempt to establish whether cells were especially sensitive to 50 Hz magnetic field exposure in any particular phase of the cell cycle. Accordingly, cells were pseudosynchronized in G0/G1 by serum deprivation and exposed for 20 min to a 50 Hz magnetic field, at 10 microT for lymphoid cells and 1 mT for HL60 cells. No significant difference was observed between the c-myc transcript levels of control and exposed cells for either of the synchronized cell types. These results for synchronized cells correlated with those for nonsynchronized cells.

[Demonstration of a protector effect of interleukin-1 against hematologic toxicity of azidothymidine (AZT)]. / Mise en évidence d'un effet protecteur de l'Interleukine-1 vis-à-vis de la toxicité hématologique de l'azidothymidine (AZT).

3'-azido-3'-deoxythymidine (Azidothymidine or AZT) has attained wide critical utility in the treatment of acquired immunodeficiency syndrome (AIDS). Unfortunately, treatment with AZT is associated with the development of severe hematopoietic toxicity. The AZT sensitivity of marrow progenitors was different with an IC 50 of 10(-8) M and 10(-6) M for respectively BFU-E and CFU-GM/GEMM. Data reported here show that recombinant human interleukin-1 alpha (IL-1 alpha), a pleiotropic cytokine, was demonstrated to be efficient to protect normal human as well as murine hematopoietic progenitors (CFU-GM, CFU-GEMM and BFU-E) from the toxic effect of AZT. The maximal effect was observed with 30 U/ml (Human cells) or 100 U/ml (murine cells) IL-1 alpha for BFU-E and CFU-GM/GEMM, with a marked effect at 1 U/ml. The results demonstrate that marrow progenitors respond differently to AZT and point out the potential efficacy of IL-1 alpha to enhance the proliferation of hematopoietic stem cells treated with growth factors (IL-3, erythropoietin) and to minimize the hematopoietic toxicity associated with AZT treatment.