Differential modulation of annexin I binding sites on monocytes and neutrophils.

Specific binding sites for the anti-inflammatory protein annexin I have been detected on the surface of human monocytes and polymorphonuclear leukocytes (PMN). These binding sites are proteinaceous in nature and are sensitive to cleavage by the proteolytic enzymes trypsin, collagenase, elastase and cathepsin G. When monocytes and PMN were isolated independently from peripheral blood, only the monocytes exhibited constitutive annexin I binding. However PMN acquired the capacity to bind annexin I following co-culture with monocytes. PMN incubation with sodium azide, but not protease inhibitors, partially blocked this process. A similar increase in annexin I binding capacity was also detected in PMN following adhesion to endothelial monolayers. We propose that a juxtacrine activation rather than a cleavage-mediated transfer is involved in this process. Removal of annexin I binding sites from monocytes with elastase rendered monocytes functionally insensitive to full length annexin I or to the annexin I-derived pharmacophore, peptide Ac2-26, assessed as suppression of the respiratory burst. These data indicate that the annexin I binding site on phagocytic cells may have an important function in the feedback control of the inflammatory response and their loss through cleavage could potentiate such responses.

Novel pathways for glucocorticoid effects on neutrophils in chronic inflammation.

Neutrophils have been implicated in mediating much of the tissue damage associated with chronic inflammatory diseases such as rheumatoid arthritis, where they are involved in destruction of both cartilage and bone. Glucocorticoids are powerful anti-inflammatory agents, often used in the treatment of this autoimmune disease. They exert significant inhibitory effects on neutrophil activation and functions, such as chemotaxis, adhesion, transmigration, apoptosis, oxidative burst, and phagocytosis. The mechanisms by which glucocorticoids exert these effects on neutrophils are unclear. Evidence from studies of inflammation in human subjects and animal models suggests that annexin-I an endogenous, glucocorticoid-induced protein also known as lipocortin-1, has a pivotal role in modulating neutrophil activation, transmigratory, and phagocytic functions. Furthermore, we present evidence for altered neutrophil functions in rheumatoid arthritis that correspond to a significantly reduced capacity of these cells to bind annexin-I. A proposed novel pathway for glucocorticoid actions on neutrophils involving annexin-I could explain the development of chronic neutrophil activation in diseases such as rheumatoid arthritis.

Effect of a neurokinin-1 (NK1) receptor antagonist on oedema formation induced by tachykinins, carrageenin and an allergic response in guinea-pig skin.

The effect of the neurokinin-1 (NK1) receptor antagonist RP67580 in modulating inflammatory oedema formation has been investigated in guinea-pig skin. Oedema formation was measured over 30 min by the extravascular accumulation of intravenously-injected 125I-albumin in the anaesthetised guinea-pig. RP67580 was injected intradermally with the agents under test. Intradermal RP67580 (10 nmol/site) inhibits oedema formation induced by substance P (30 pmol) and neurokinin A (100 pmol), but not that induced by bradykinin (10-1000 pmol) or histamine (10 nmol). Substance P-induced oedema formation is similar in control (saline) and mepyramine (histamine H1 receptor antagonist) pretreated guinea-pigs suggesting a minimal involvement of histamine in substance P induced oedema formation in guinea-pig skin. Oedema formation induced by intradermal carrageenin (0.2%) was not inhibited by RP67580 (1-10 nmol). A significant but partial inhibition of oedema formation induced in a passive cutaneous anaphylaxis (PCA) response was observed. The oedema formation in the PCA was inhibited 50% by mepyramine pretreatment but in the presence of mepyramine no further inhibition of the PCA response by RP67580 was observed.