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In acute inflammation, infiltration of neutrophils often precedes a second phase of monocyte invasion, and data in the literature suggest that neutrophils may directly stimulate mobilization of monocytes via neutrophil granule proteins. In this study, we present a role for neutrophil-derived heparin-binding protein (HBP) in monocyte arrest on endothelium. Adhesion of neutrophils to bovine aorta endothelial cells (ECs) or HUVEC-triggered secretion of HBP and binding of the protein to the EC surface. Blockade of neutrophil adhesion by treatment with a mAb to CD18 greatly reduced accumulation of HBP. In a flow chamber model, immobilized recombinant HBP induced arrest of human monocytes or monocytic Mono Mac 6 (MM6) cells to activated EC or plates coated with recombinant adhesion molecules (E-selectin, P-selectin, VCAM-1). However, immobilized recombinant HBP did not influence arrest of neutrophils or lymphocytes. Treatment of MM6 cells with recombinant HBP evoked a rapid and clear-cut increase in cytosolic free Ca2+ that was found to be critical for the HBP-induced monocyte arrest inasmuch as pretreatment with the intracellular calcium chelating agent BAPTA-AM abolished the evoked increase in adhesion. Thus, secretion of a neutrophil granule protein, accumulating on the EC surface and promoting arrest of monocytes, could contribute to the recruitment of monocytes at inflammatory loci.

The gut immune system is an essential part of the bamer function of the gut wall. The uptake of microbial and nutritional antigens in the gut starts immune responses by initiating either tolerance or a specific secretory immune reaction (for review see refs. 1-4). Large numbers of lymphocytes are distributed in the epithelium and LP of the gut mucosa. Some of the LP lymphocytes are PP-derived B lymphoblasts, becoming mature plasma cells in the LP. They preferentially produce IgA (5, 6). The majority of T cells in the LP are CD4+ (7,8). The T cells show a high expression of genes associated with cell activation (9). The proportion of antigen-primed memory cells is higher in LP T cells than in peripheral blood lymphocytes (reviewed in 4).In the early postnatal period, the gut wall is exposed to microbial antigens for the first time. Additionally, the amount of

The indolo[2,1- b]quinazoline alkaloid tryptanthrin has previously been identified as the cyclooxygenase-2 (COX-2) inhibitory principle in the extract ZE550 prepared from the medicinal plant Isatis tinctoria (Brassicaceae). We here investigated the potential inhibitory activity of tryptanthrin and ZE550 on COX-2, COX-1 in cellular and cell-free systems. A certain degree of selectivity towards COX-2 was observed when COX-1-dependent formation of thromboxane B(2) (TxB(2)) in HEL cells and COX-2-dependent formation of 6-ketoprostaglandin F(1alpha) (6-keto-PGF(1alpha)) in Mono Mac 6 and RAW 264.7 cells were compared. Preferential inhibition of COX-2 by two orders of magnitude was found in phorbol myristate acetate (PMA) activated bovine aortic coronary endothelial cells (BAECs). Assays with purified COX isoenzymes from sheep confirmed the high selectivity towards COX-2. The leukotriene B(4) (LTB(4)) release from calcium ionophore-stimulated human granulocytes (neutrophils) was used as a model to determine 5-lipoxygenase (5-LOX) activity. Tryptanthrin and the extract ZE550 inhibited LTB(4) release in a dose dependent manner and with a potency comparable to that of the clinically used 5-LOX inhibitor zileuton.

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The altered neutrophil defense might play a key role in the pathogenesis of bisphosphonate-associated osteonecrosis of the jaws, although the underlying causation between inflammatory reaction and the development of necrosis is yet unknown.

Angiotensin-converting enzyme (ACE) inhibitors interfere with several key events of vascular inflammation resulting in impressive reductions in coronary vascular events. However, in human arteries ACE inhibitors block the production of angiotensin II (AngII) incompletely because of the involvement of alternative pathways in local AngII formation. Therefore, our study concentrated on the presumed modulation by ACE inhibition of local AngII-mediated inflammatory actions by a mechanism independent of blockage of AngII formation. We analyzed the effect of the ACE inhibitor ramiprilat on AngII-dependent cell adhesion molecule (CAM) expression and adhesion of monocytic THP-1 cells to endothelial cells. AngII induced upregulation of P-selectin, VCAM-1 and ICAM-1 on endothelial cells via activation of AT1, which was correlated with enhanced THP-1 adhesion in flow chamber assays. Both enhanced adhesion and adhesion molecule expression were significantly reduced by pretreatment with ramiprilat. Ramiprilat reduced AT1 expression on endothelial cells and decreased the AngII-induced p65 translocation into the nucleus. Diminished AT1 expression and adhesion molecule expression in response to ramiprilat treatment were partially reversed after incubation with a bradykinin 2 receptor antagonist, suggesting that elevated bradykinin levels under ACE inhibition may be involved in the beneficial effect of ACE inhibitors. Thus, modulation of the local AngII system by ramiprilat may at least in part contribute to the benefits of ACE inhibition in the treatment of atherosclerotic diseases.

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