Alpha‐globulins suppress human leukocyte tumor necrosis factor secretion

Abstract

The secretion of tumor necrosis factor (TNF) by human peripheral blood mononuclear cells was suppressed by either whole human plasma alpha-globulins or purified alpha 1-acid-glycoprotein, alpha 1-antitrypsin and alpha 2-macroglobulin in a concentration-dependent manner. alpha 1-Antitrypsin was found to be the most suppressive of the purified proteins tested and completely blocked TNF release at concentrations above 1.25 mg/ml. Both alpha 1-acid glycoprotein and alpha 1-antitrypsin blocked TNF secretion by leukocytes which were simultaneously stimulated with either recombinant human interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS). IFN-gamma- and LPS-activated cells were also susceptible to suppression mediated by these two alpha-globulins and the inhibition produced by 5 mg/ml alpha 1-antitrypsin was greater than that caused by either 1 microM prostaglandin E2 or 10 ng/ml transforming growth factor-beta 1. The level of TNF mRNA in TNF-secreting and alpha-globulin-suppressed cells was examined and found to be equal in both groups. The suppressive effect of whole alpha-globulins was confined to the inhibition of TNF secretion and these plasma proteins had no effect on the cytolytic activity of the recombinant cytokine as measured on murine L-929 target cells. Thus the alpha-globulins, which are a major fraction of the circulating plasma proteins, may function in TNF homeostasis by controlling TNF secretion without inhibiting the biological activity of the released cytokine.

Enhancement of lipopolysaccharide-induced tumor necrosis factor secretion by hyperimmune serum from chronic infected patients

“…The inactivation of small amounts of S. abortus equi LPS (0.01 gg/ml) by serum from healthy controls described in this study supports previous studies, in which the LPS-induced IL-1 or TNF response was inhibited by normal human serum or purified serum proteins as lipoproteins, IgG or alpha globulins [9,13,38]. Interesting!y, NHS seemed to have a slightly neutralizing effect on even high concentrations ofP.…”

“…Inhibition of LPS effects by serum from healthy donors has been demonstrated by several authors [13,27,38,41], using the Limulus amebocyte lysate assay. Under certain conditions interaction of serum with LPS has also been shown to prevent LPS-induced mediator release [5,9,29,42] and this inhibitory effect has been shown to involve the lipoprotein fraction of the serum [9], the alpha globulins [38] and naturally occurring IgG anti-LPS antibodies [13].…”

Converting enzyme-independent release of tumor necrosis factor α and IL-1β from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3

“…This observation indicates that PR3 acts independently of the action of these converting enzymes and most likely at the most distal points of these pathways. Furthermore PR3 previously has been shown to process an in vitro-translated precursor of TNF␣ to a biologically active form (23), and serine protease inhibitors have been found to inhibit secretion of TNF␣ with no effect on TNF␣ mRNA (22). We also have observed that PR3 can process recombinant pro-IL-1␤ to a biologically active form (unpublished observations).…”

“…The neutrophil-derived proteinases, NE and Cat G, as well as members of the matrix metalloproteinase family, granzyme A and human mast cell chymase, have been shown to cleave recombinant pro-IL-1␤ in vitro (9,(18)(19)(20)(21). Serine protease inhibitors were found to inhibit secretion of TNF␣ but had no effect on levels of TNF␣ mRNA (22). Moreover, an alternative processing mechanism for the release of membrane-bound TNF␣ has been described by using an in vitro translated precursor of TNF␣.…”

In Vitro Processing of Human Tumor Necrosis Factor-α

“…Interestingly, PR-3 is present in large amounts in the serum of normal subjects and its levels are significantly high in patients with connective tissue disease (36). Along with this line, the serine proteinase inhibitor ␣ 1 -AT was shown to block TNF-␣ release in vitro (37) and in vivo (8). More recently, the TNF-␣ concentration in synovial fluid of rheumatoid arthritis patients was shown to be inversely correlated with ␣ 1 -AT activity (38).…”