Abstract
The development of LPS tolerance has been suggested to be mediated by an inhibition of cytokine synthesis. Here we have studied serum IL-6 and TNF levels in mice after LPS administration. Repeated administration of LPS (35 μg daily for 4 days) to mice induced a refractoriness (tolerance) to subsequent administrations of LPS in terms of induction of circulating IL-6 and TNF. To investigate the mechanism by which LPS down-regulates its own induction of cytokine synthesis and the relationship between IL-6 and TNF production, we attempted to revert the inhibition of IL-6 and TNF production using agents like PMA or IFN-γ, previously reported to activate macrophage production of cytokines. Pretreatment with PMA (4 μg, 10 min before LPS) partially restored IL-6 production in LPS-tolerant mice given 2 μg LPS. On the other hand, PMA did not restore TNF induction in LPS-tolerant mice, even when administered with high doses of LPS (up to 200 μg). A similar reversal of LPS resistance to IL-6, but not TNF, induction by PMA was observed in genetically LPS-resistant C3H/HeJ mice. IFN-γ also restored, although to a lesser extent than PMA, IL-6 production. However, unlike PMA, IFN-γ could also partially restore TNF production in LPS-tolerant mice, although only when LPS was administered at high doses. By contrast with PMA, IFN-γ was clearly more active in restoring TNF synthesis than that of IL-6. Similar results were obtained in genetically LPS-unresponsive C3H/HeJ mice. These data Jggest that different mechanisms are implicated in the inhibition of IL-6 and TNF synthesis in LPS-tolerant mice and that part of this inhibition can be overcome by PMA or IFN-γ.
| Original language | English |
|---|---|
| Pages (from-to) | 899-902 |
| Number of pages | 4 |
| Journal | Journal of Immunology |
| Volume | 147 |
| Issue number | 3 |
| Publication status | Published - Aug 1 1991 |
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Cite this
Reversal of defective IL-6 production in lipopolysaccharide-tolerant mice by phorbol myristate acetate. / Mengozzi, Manuela; Sironi, Marina; Gadina, Massimo; Ghezzi, Pietro.
In: Journal of Immunology, Vol. 147, No. 3, 01.08.1991, p. 899-902.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Reversal of defective IL-6 production in lipopolysaccharide-tolerant mice by phorbol myristate acetate
AU - Mengozzi, Manuela
AU - Sironi, Marina
AU - Gadina, Massimo
AU - Ghezzi, Pietro
PY - 1991/8/1
Y1 - 1991/8/1
N2 - The development of LPS tolerance has been suggested to be mediated by an inhibition of cytokine synthesis. Here we have studied serum IL-6 and TNF levels in mice after LPS administration. Repeated administration of LPS (35 μg daily for 4 days) to mice induced a refractoriness (tolerance) to subsequent administrations of LPS in terms of induction of circulating IL-6 and TNF. To investigate the mechanism by which LPS down-regulates its own induction of cytokine synthesis and the relationship between IL-6 and TNF production, we attempted to revert the inhibition of IL-6 and TNF production using agents like PMA or IFN-γ, previously reported to activate macrophage production of cytokines. Pretreatment with PMA (4 μg, 10 min before LPS) partially restored IL-6 production in LPS-tolerant mice given 2 μg LPS. On the other hand, PMA did not restore TNF induction in LPS-tolerant mice, even when administered with high doses of LPS (up to 200 μg). A similar reversal of LPS resistance to IL-6, but not TNF, induction by PMA was observed in genetically LPS-resistant C3H/HeJ mice. IFN-γ also restored, although to a lesser extent than PMA, IL-6 production. However, unlike PMA, IFN-γ could also partially restore TNF production in LPS-tolerant mice, although only when LPS was administered at high doses. By contrast with PMA, IFN-γ was clearly more active in restoring TNF synthesis than that of IL-6. Similar results were obtained in genetically LPS-unresponsive C3H/HeJ mice. These data Jggest that different mechanisms are implicated in the inhibition of IL-6 and TNF synthesis in LPS-tolerant mice and that part of this inhibition can be overcome by PMA or IFN-γ.
AB - The development of LPS tolerance has been suggested to be mediated by an inhibition of cytokine synthesis. Here we have studied serum IL-6 and TNF levels in mice after LPS administration. Repeated administration of LPS (35 μg daily for 4 days) to mice induced a refractoriness (tolerance) to subsequent administrations of LPS in terms of induction of circulating IL-6 and TNF. To investigate the mechanism by which LPS down-regulates its own induction of cytokine synthesis and the relationship between IL-6 and TNF production, we attempted to revert the inhibition of IL-6 and TNF production using agents like PMA or IFN-γ, previously reported to activate macrophage production of cytokines. Pretreatment with PMA (4 μg, 10 min before LPS) partially restored IL-6 production in LPS-tolerant mice given 2 μg LPS. On the other hand, PMA did not restore TNF induction in LPS-tolerant mice, even when administered with high doses of LPS (up to 200 μg). A similar reversal of LPS resistance to IL-6, but not TNF, induction by PMA was observed in genetically LPS-resistant C3H/HeJ mice. IFN-γ also restored, although to a lesser extent than PMA, IL-6 production. However, unlike PMA, IFN-γ could also partially restore TNF production in LPS-tolerant mice, although only when LPS was administered at high doses. By contrast with PMA, IFN-γ was clearly more active in restoring TNF synthesis than that of IL-6. Similar results were obtained in genetically LPS-unresponsive C3H/HeJ mice. These data Jggest that different mechanisms are implicated in the inhibition of IL-6 and TNF synthesis in LPS-tolerant mice and that part of this inhibition can be overcome by PMA or IFN-γ.
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M3 - Article
C2 - 1907307
AN - SCOPUS:0025744564
VL - 147
SP - 899
EP - 902
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -