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The specific adhesion of cells to other cells or to extracellular matrices is a basic component of cell migration and recognition, and it underlies a lot of biologic processes including embryogenesis, tissue repair, and both immune and inflammatory responses. The aim of this study was to investigate the influence of female steroid hormones on expression of the adhesion molecules on the leukocytes. The whole blood from healthy people was incubated in a presence or an absence of progesterone (2 micrograms/ml) or 17 beta-estradiol (0.2 microgram/ml) for 4 h., and then with TNF for 18 h. The phenotype of the leukocytes was investigated by flow cytometry. Progesterone inhibited an expression of CD54 on monocytes and lymphocytes due to reducing density of these molecules on the cellular surface; 17 beta-estradiol inhibited an expression of CD54 on monocytes and CD69 molecules on monocytes and lymphocytes due to reducing density of these molecules on the cellular surface. Progesterone inhibited TNF-stimulated CD54 and CD11b expression on the granulocytes and CD69 expression on lymphocytes by reducing partly the density of these molecules on the surface of cells, and in such way it partly blocked the proinflammatory activity of this cytokine. Progesterone also reduced CD62L expression on the granulocytes by reducing an amount of a marker, positive to those cells but enhanced the effect of TNF. The data obtained evidence that female steroid hormones take part in the regulation of an expression of adhesion molecules by the leukocytes and are likely to be important in the circulation and activation of the leucocytes.

The lymphocyte proliferation is multicomponent mechanism of immune system reactivity. Many costimulatory factors take part in this process. Proinflammatory cytokines (TNF, IL-1 alpha and beta) enhance proliferation of activated lymphocytes. Female steroid hormones inhibit proliferation of mitogen and alloantigen-activated lymphocytes. The aim of this study was to investigate the effect of progesterone and 17 beta-estradiol on the costimulatory proliferative activity of proinflammatory cytokines in vitro. Female steroid hormones inhibit lymphocyte response to antiCD3 antibody. Progesterone had a stronger effect than 17 beta-estradiol (64 and 13% of inhibition respectively). 17 beta-estradiol enhanced the TNF costimulatory effect on the lymphocyte proliferation. Progesterone neutralized this TNF-induced effect and reverted it (inhibition of lymphocyte proliferation was enhanced in the presence of TNF). We found dominant inhibitory effect of progesterone on the TNF costimulatory activity when progesterone and estrogen were added simultaneously. Progesterone and 17 beta-estradiol downregulated costimulatory proliferative activity of IL-1 alpha or beta. Thus female steroid hormones had suppressive effect on the antiCD3-stimulated lymphocyte proliferation. They downregulated costimulatory proliferative activity of IL-1 alpha/beta and had opposite effect on TNF costimulatory activity. Our results suggest possible roles female steroid hormones as regulators on activity of proinflammatory cytokines and their functions in lymphocyte proliferation.

The panel of 23 newly produced monoclonal antibodies (mAbs) against human tumor necrosis factor (TNF) was examined for enhanced or cooperative TNF binding. Epitopic mapping revealed a preferential mAb generation against two epitopes designed as A1 and C1. Both A1 and C1 mAbs have neutralizing activity and display remarkable property to bind TNF synergistically comprising a pair of cooperative mAbs. C1 epitope resides within the TNF receptor-binding site (RBS) and responsible for generation of competitive neutralizing mAbs that block TNF activity by direct RBS masking. RBS-distal A1 epitope represents allosteric neutralizing mAbs that block TNF activity by conformational RBS changes. Combination of A1 and C1 mAbs resulted in synergistic TNF neutralization through complementary effect of competitive and allosteric TNF blocking mechanisms. Generation of cooperative Abs may have significance to achieve the most efficient neutralization of protein antigens with an intolerable functional activity in vivo.