C5a induction of human interleukin 1. Synergistic effect with endotoxin or interferon-gamma.

Abstract

Interleukin-1 (IL-1) is a potent cytokine which possesses the ability to mediate systemic acute phase responses as well as local tissue inflammation. In these studies, we have examined the ability of C5a and C5a des Arg to induce IL-1 production in vitro. Human C5a and C5a des Arg were purified to homogeneity and were found to stimulate IL-1 release from freshly obtained human mononuclear cells into the extracellular medium. Only 2 hr of exposure to the purified complement components were necessary in order to stimulate IL-1 production. The minimal concentration of C5a required was 25 ng/ml, whereas 125 ng/ml of C5a des Arg induced comparable amounts of IL-1. This dose relationship was maintained at higher concentrations (150 ng/ml vs 750 ng/ml, respectively). That the effect was due to the anaphylatoxins themselves, and not endotoxin contamination, was shown by negative Limulus amebocyte lysate tests and employing preincubation of C5a/C5a des Arg with polymyxin B. The latter blocked a wide dose range of endotoxin-stimulated IL-1 production. However, when endotoxin was added to C5a or C5a des Arg, significant synergism in the stimulation of IL-1 production was observed, occurring at various concentrations of either agent. A similar synergism with C5a/C5a des Arg was seen with interferon-gamma. In these studies, IL-1 production was measured by bioassay employing cloned D . 10 . G4 . 1 murine T cells and by radioimmunoassay for human IL-1 beta; using C5a/C5a des Arg as stimulants, there was a high degree of correlation (r = 0.82) between the two assays. Since traumatic, infectious, and inflammatory diseases may result in the simultaneous appearance of these stimuli, the synergism described herein is likely to be clinically relevant.

Serum Depletion of Complement Component 5a Is Associated With Increased Inflammation and Poor Clinical Outcomes in Patients With Perianal Fistulas

“…Then, we evaluated the expression of the cytokine IL-1β, a surrogate marker of inflammation and downstream target of C5a. 11,12 Consistent with our previous observations, IL-1β was also significantly increased in the persistent fistulas and had a strong, positive, linear association with expression of C5a (Figs. 3D and E).…”

The metabolic effects of thermal injury

“…Presently, rapidly emerging evidence exists for the generation of polypeptide cytokines which have been isolated in burn patients' wounds and serum and have profound effects upon regional and whole body metabolism. IL-I has been isolated from blister fluid in burned tissue [t48] and likely is released by damaged epithelial cells directly [149] or by indirect stimulation of heat denatured tissue after activation of the classical and alternative pathways of the complement system [150,151]. Similarly, tumor necrosis factor has been isolated from the plasma of burned patients [152], levels of which closely correlate with the severity of injury.…”