CD69, also known as activation inducer molecule, very early activation antigen, MLR-3 and Leu-23, is a member of the natural killer (NK) cell gene complex family of signal transducing receptors. CD69 is as a type II transmembrane glycoprotein with a C-type lectin binding domain in the extracellular portion of the molecule. CD69 expression is induced in vitro on cells of most hematopoietic lineages, including T and B lymphocytes, NK cells, murine macrophages, neutrophils and eosinophils, while it is constitutively expressed on human monocytes, platelets and epidermal Langerhans cells. Although a specific ligand for CD69 has not been identified, its wide cellular distribution and the induction of intracellular signals upon CD69 crosslinking suggest a role for the receptor in the biology of hematopoietic cells. Moreover, certain results indicate that CD69 may be involved in the pathogenesis of such diseases as rheumatoid arthritis, chronic inflammatory liver diseases, mild asthma, and acquired immunodeficiency syndrome.
The bactericidal/permeability-increasing protein (BPI) inhibits the lipopolysaccharide (LPS)-mediated activation of monocytes. Due to its inhibitory activity for various LPS, BPI has therapeutic potential in endotoxic shock. To be efficient in vivo, BPI should overcome the action of LPS-binding protein (LBP), a serum molecule that increases the expression of LPS-inducible genes via CD 14 of monocytes. rBPI 23 , a recombinant fragment of BPI, prevented in a dose-dependent manner the binding and the internalization of LPS mediated by LBP. Consequently, rBPI 23 also inhibited LPS-induced tumor necrosis factor (TN Fa) synthesis from monocytes. LPS-and LBP-mediated activation of monocytes was totally inhibited when LPS was preincubated with rBPI 23 • Adding rBPI 23 at the same time as LBP resulted in an important but partial inhibition of TNFa release, but this inhibition vanished with delaying the time of addition of rBPI 23 • These studies suggest that the inhibitory activity of BPI is related to its ability to compete with LBP for LPS.Living organisms have developed several protective mechanisms against toxic lipopolysaccharide (LPS) of gram-negative bacteria. Very recently, two members ofa family of proteins have been recognized that possess LPS-binding sites. Indeed, the LPS-binding protein (LBP) and the bactericidalf permeability-increasing protein (BPI) share the ability to bind to smooth and rough LPS as well as to lipid A [1, 2]. There is a striking homology in the DNA sequence of the two human, rabbit, or bovine proteins [3]. However, despite their structural similarities, the functions of LBP and BPI appear an tagonistic.Most circulating LPS binds to plasma LBP, and LPS linked to LBP is transferred to CD 14 on the surface of cells of the monocytic lineage and neutrophils, resulting in increased expression of LPS-inducible genes [3,4]. LBP-mediated processes include increased tumor necrosis factor-a (TNFa) production by monocytes [3][4][5], accelerated priming of neutrophils for the oxidative response to FMLP [6], and increased adhesive capacity of complement receptor CR3 of neutrophils [7]. LBP was originally described as an acutephase reactant in the rabbit [8] . Soluble BPI, recombinant BPI, or its 25-kDa N-terminal fragment have been shown to inhibit endotoxin activity by neutralizing LPS, as detected by the inhibition of the proteolytic cascade in the limulus amebocyte lysate assay, by the inhibition of the priming of neutrophils by LPS, and by the inhibition of LPS-mediated production of TNFa by monocytes [11][12][13]. Because of the apparent antagonistic properties of these two proteins that bind LPS, it is important to better define the respective roles of LBP and BPI in the LPS-induced activation process, inasmuch as BPI has therapeutic potential in endotoxic shock. We characterized in vitro the direct competition between LBP and BPI for binding ofLPS to cells of the monocytic lineage and investigated the competition between these two molecules in the activation process of monocytes resulting in TN...
Calcium ionophore A23187 can mimic IFN-gamma-induced macrophage activation for intracellular Leishmania killing and secretion of L-arginine-derived nitrite. Because the effects of ionophore are not restricted to calcium mobilization but also involve alterations of phospholipid metabolism, we have examined the role of PGE2 in the activation process. Macrophages exposed to A23187 or IFN-gamma in the presence of LPS and FCS secreted significant amounts of PGE2 independently of the presence of L-arginine in the incubation medium. The addition of the cyclooxygenase inhibitor indomethacin or omission of FCS abrogated PGE2 secretion but had little effect on nitrite production or intracellular killing. The addition of exogenous PGE2, of agents increasing PGE2 production such as arachidonic acid and colchicine, or of an analogue of cAMP, dibutyryl cAMP inhibited A23187 + LPS-induced activation whereas that mediated by IFN-gamma + LPS remained unimpaired. Our results indicate that PGE2 can modulate activation induced by A23187 but not by IFN-gamma, probably by a process involving cAMP. Conceivably, ionophore can mimic IFN-gamma for the induction of activation but lacks the capacity to help maintain the activated state because of its inability to desensitize macrophages to negative regulation by PGE2, as suggested previously for IFN-gamma-dependent activation.
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