Interleukin 6 Modulates lnterleukin-1– and Stress-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis in Male Rats

Abstract

This study examined the interaction between interleukin 6 (IL-6) and IL-1 and between IL-6 and stress on the activation of the hypothalamic-pituitary-adrenal (HP A) axis. Coadministration of IL-6 (100 ng/rat) with IL-1 (20 or 100 ng/ rat) resulted in synergistic stimulation of the HPA axis, as determined by increased plasma levels of ACTH and corticosterone (CORT) which were greater in rats that received both cytokines than in rats receiving either cytokine alone. Concomitant administration of IL-6 (100 ng/rat) with exposure to a novelty stressor also synergistically stimulated the activation of the HPA axis, as IL·6-treated rats subjected to novelty stress had greater increases in plasma levels of ACTH and CORT than vehicle-treated rats exposed to novelty stress or rats receiving IL-6 alone. However, concomitant administration of IL-6 (100 ng/rat) did not significantly affect restraint stress induced elevation of plasma levels of ACTH and CORT, although IL-6 tended to prolong restraint stress induced elevation of plasma levels of CORT. These findings indicate a modulatory role for IL-6 stimulated HPA axis activity in response to IL-1 or a novelty psychological stressor, but not for restraint stress.

Synergistic Effects of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-α Central Monoamine, Corticosterone, and Behavioral Variations

“…While IL-1␤ and IL-6 synergistically influenced ACTH and corticosterone, depending on the timing of their administration (Perlstein et al 1991;Zhou et al 1996), such an outcome was not apparent in the present investigation. Moreover, in independent experiments there was no evidence of a synergism irrespective of whether blood was collected 30 min or 1 hr after treatment.…”

“…As indicated earlier, since IL-1␤ and IL-6 may synergistically influence HPA activity, depending on the timing of their administration (Perlstein et al 1991;Zhou et al 1996), an additional experiment assessed whether these cytokines would synergistically influence plasma corticosterone when blood was taken 30 min after treatment. The procedure was identical to that of the preceding study, except that mice were decapitated 30 min after administration of either vehicle (two successive i.p.…”

“…The behavioral effects of endotoxin and cytokine treatment are paralleled by increased hypothalamic-pituitary-adrenal (HPA) activity, as reflected by increased activity of corticotropin releasing hormone (CRH) and elevated plasma ACTH and corticosterone levels (Kakucksa et al 1993;Tilders et al 1993). Inasmuch as cytokines elicit several effects similar to those of LPS, it has been assumed that at least some of the endotoxin effects involve IL-1 ␤ , or this cytokine acting conjointly or synergistically with IL-6 and/or TNF-␣ (Dunn 1992a; Ebisui et al 1994;Long et al 1990;Zanetti et al, 1992;Zhou et al 1996). Indeed, IL-1 ␤ and IL-6 synergistically increased plasma corticosterone (Zhou et al 1996) and ACTH (Matta et al 1992;Perlstein et al 1991), whereas IL-1 ␤ and TNF-␣ synergistically stimulated IL-11 through the production of prostaglandin-E2 in rheumatoid synovial fibroblasts (Mino et al 1998).…”

“…The relatively high level of plasma corticosterone observed in this particular study was surprising, as this dose of IL-1␤ ordinarily provoked plasma corticosterone concentrations in the 10-15 g/dl range (see Experiment 1, and ensuing experiment). As indicated earlier, the 0.025 g dose of IL-1␤ elicited effects that were just at threshold (see Experiment 1) and thus may have been subject to greater variability.As indicated earlier, since IL-1␤ and IL-6 may synergistically influence HPA activity, depending on the timing of their administration (Perlstein et al 1991;Zhou et al 1996), an additional experiment assessed whether these cytokines would synergistically influence plasma corticosterone when blood was taken 30 min after treatment. The procedure was identical to that of the preceding study, except that mice were decapitated 30 min after administration of either vehicle (two successive i.p.…”

“…Inasmuch as cytokines elicit several effects similar to those of LPS, it has been assumed that at least some of the endotoxin effects involve IL-1 ␤ , or this cytokine acting conjointly or synergistically with IL-6 and/or TNF-␣ (Dunn 1992a;Ebisui et al 1994;Long et al 1990;Zanetti et al, 1992;Zhou et al 1996). Indeed, IL-1 ␤ and IL-6 synergistically increased plasma corticosterone (Zhou et al 1996) and ACTH (Matta et al 1992;Perlstein et al 1991), whereas IL-1 ␤ and TNF-␣ synergistically stimulated IL-11 through the production of prostaglandin-E2 in rheumatoid synovial fibroblasts (Mino et al 1998). As well, IL-1 ␤ and TNF-␣ synergistically reduced blood glucose levels (Vogel et al 1991), social exploration (Bluthe et al 1994), and food intake Sonti et al 1996;Yang et al 1994), and increased the levels of inducible nitric oxide synthase (Kuemmerle 1998).…”