Engaging anti-inflammatory mechanisms and triggering inflammatory effector apoptosis during Familial Mediterranean Fever attack.

OBJECTIVE: To investigate endotoxin-induced tolerance, intracellular cytokine synthesis polarization and monocyte apoptosis during Familial Mediterranean Fever (FMF). METHODS: Lipopolysaccharide (LPS)-induced tolerance, intracellular cytokine synthesis and monocyte apoptosis were determined in FMF patients by flow cytometry using whole blood cell culture technique. RESULTS: Endotoxin homo- and cross-tolerance, detected as the percentage of TNF-alpha synthesizing monocytes, developed in whole blood preparations of patients in attack period, but not during remission. The induction of anti-inflammatory cytokine synthesis polarization and enhancement of iodine-lithium-alpha-dextrin- and LPS-induced monocyte apoptosis was observed in FMF patients during the attack, whereas monocytes from patients in remission period exhibited proinflammatory cytokine polarization and resistance to the repeated LPS-induced apoptosis. Colchicine induced anti-inflammatory cytokine synthesis and caused down-modulation of monocyte apoptosis, whereas cytokines did not alter LPS-induced monocyte apoptosis. CONCLUSION: The self-limited nature of attacks during FMF may represent periods of inflammation resolution compensatory to continued sub-clinical inflammation during the remission.

Hypothalamic proline-rich polypeptide enhances bone marrow colony-forming cell proliferation and stromal progenitor cell differentiation.

The AGAPEPAEPAQPGVY proline-rich peptide (PRP-1) was isolated from neurosecretory granules of the bovine neurohypophysis; it is produced by N. supraopticus and N. paraventricularis. It has been shown that PRP-1 has many potentially beneficial biological effects, including immunoregulatory, hematopoietic, antimicrobial, and antineurodegenerative properties. Here we showed that PRP increased colony-forming cell (CFC) proliferation in rat bone marrow (BM) cells in vivo. In PRP-treated rat BM, the CFU number at day 7 and day 14 was considerably increased in comparison with untreated rat BM and no difference was found at day 21 and day 28. The related peptide [arg8]vasopressin did not reveal CFC proliferation. PRP failed to farther increase CFC proliferation in vitro in BM obtained from PRP-treated or untreated rats. After 3-4 days of human BM stromal cell cultivation in the presence of 2-20 microg/ml PRP the appearance of cells expressing CD15, CD10, CD11a, CD11b, CD3, CD4, and CD16 surface antigens did not differ from the untreated cells. PRP increased the appearance of CD14-positive cells upon 3-4-day incubation with both adult and fetal BM stromal cells. Our results suggest a previously undescribed role for the hypothalamic peptide within neurosecretory hypothalamus-bone marrow humoral axis, because PRP enhances BM colony-forming cell proliferation and stromal cell differentiation.

The effects of adriamycin and adriamycin complexes with transitional metals on Ca(2+)-dependent K+ channels of human erythrocytes.

The influence of adriamycin (ADR) and ADR complexes with transitional metals Fe2+, Cu2+ and Co2+ on Ca(2+)-dependent K+ channels of human erythrocytes was investigated. We show that the anthracycline moiety of ADR increases Ca(2+)-dependent K+ efflux from erythrocytes, induced by low concentrations of propranolol, while the whole molecule of ADR has not any effect on Ca(2+)-dependent K+ channels, induced by propranolol or A23187 and on Pb(2+)-dependent K+ efflux. Ethidium bromide, verapamil and trifluoroperazine inhibited Ca(2+)-dependent K+ efflux, induced by high doses of propranolol. The anthracycline moiety of ADR is able to abolish blocking effect of ethidium bromide and verapamil, but does not influence the blocking effect of trifluoroperazine. We further show that ADR complexes with Fe2+, Cu2+ and Co2+ are potent inhibitors of Ca(2+)-dependent K+ efflux, induced by propranolol, but not of Pb(2+)-dependent K+ efflux. On the contrary, ADR-Fe3+ complex activates K(+)-permeability of human red blood cell. It is suggested that opposite effects of anthracycline moiety of ADR and ADR complexes with transitional metals on Ca(2+)-dependent K+ channels, induced by propranolol is due to their influence on the pathways of Ca2+ transport into cells, rather than their action directly on K+ channels.