BACTERIAL LIPOPOLYSACCHARIDE INDUCTION OF IL-6 IN RAT TELENCEPHALIC CELLS IS MEDIATED IN PART BY IL-1

Interleukin-6 (IL-6) appears in the cerebrospinal fluid (CSF) of patients with acute infection of the central nervous system, and in the brains and CSF of experimental animals following systemic or intracerebral injection of bacterial endotoxin (Eschericia coli lipopolysaccharide, LPS). Since LPS is known to induce secretion of interleukin-1 (IL-1) in many cell types including those of the brain, and IL-1 can induce IL-6 in brain tissue it appeared reasonable to postulate that the effects of LPS on IL-6 production were mediated through IL-1 induction. To test this hypothesis, the effects of IL-1 receptor antagonist (IL-1 Ra) on LPS and IL-1-induced IL-6 secretion were tested in a mixed brain cell culture from 17-day fetal rat, after 12-14 days in culture. IL-6 secretion was induced by IL-1beta in a concentration as low as 1 x 10(-10) M (p = 0.0008); addition of IL-1 Ra was shown to inhibit IL-1-induced changes by 8 7% (p = 0.00 12) at a molar ratio of 100: 1, and by 100% at a molar ratio of 1,000:1. LPS stimulated IL-6 secretion progressively over the concentration of 1-100 ng/ml (p = 0.0001). LPS 10 ng/ml-induced IL-6 secretion was inhibited by 66% by IL-1 Ra in a concentration of 1,000 ng/ml (p = 0.0077). The inhibitory effect of IL-1 Ra was not significantly greater even when used at a concentration of 5,000 ng/ml. These findings indicate that LPS-induced IL-6 secretion is mediated at least in part through the induction of IL-1. These findings extend to brain cells the previously reported effects of the antagonist on IL-1 responses in immunocompetent cells, and confirm the presence of functional IL-1 receptors in the central nervous system. Since IL-1 Ra has been shown to be induced by bacterial toxins, and is present in brain, it is likely that central responses to inflammation (as well as peripheral responses) are regulated by paracrine interaction between IL-1 and IL-1 Ra.