Neutralization of IL-10 increases lethality in endotoxemia. Cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor.

Abstract

The overzealous production of pro-inflammatory cytokines during endotoxemia can result in shock, multiorgan dysfunction, and even death. The extent of tissue injury that occurs in endotoxemia is determined not only by the release of pro-inflammatory cytokines, but also by the expression of endogenous counter-regulatory cytokines, such as IL-10. In this study, we defined the role of endogenously-produced IL-10 in a murine model of endotoxemia. Initial studies indicated that LPS administration to mice i.p. induces a significant time-dependent increase in plasma IL-10. Passive immunization with anti-IL-10 serum before LPS administration resulted in substantial increases in endotoxin-induced lethality. Furthermore, the inhibition of IL-10 bioactivity in vivo resulted in a greater and more sustained increase in plasma TNF and macrophage inflammatory protein-2 (MIP-2) levels, as compared with control animals, which was accompanied by early increases in lung polymorphonuclear leukocyte influx and lung capillary leak. Finally, anti-IL-10-mediated lethality was significantly abrogated by concomitant treatment with anti-MIP-2 serum and/or sTNFR:Fc alone or in combination. These observations indicate that TNF and MIP-2 are important cytokine mediators during endotoxemia, and endogenously produced IL-10 is instrumental in down-regulating the overzealous production of both TNF and MIP-2 that occurs in response to systemic endotoxin exposure.

• Authors: T J Standiford, R M Strieter, N W Lukacs, S L Kunkel
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 155 Issue 4 Pg. 2222-9 (Aug 15 1995) ISSN: 0022-1767 [Print] United States
• PMID: 7636269 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chemokine CXCL2
• Cytokines
• Lipopolysaccharides
• Monokines
• RNA, Messenger
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• Interleukin-10

Topics

• Animals
• Base Sequence
• Chemokine CXCL2
• Cytokines (biosynthesis, genetics)
• Immunization, Passive
• Interleukin-10 (analysis, immunology, physiology)
• Lipopolysaccharides (toxicity)
• Mice
• Molecular Sequence Data
• Monokines (biosynthesis, genetics)
• RNA, Messenger (analysis)
• Receptors, Tumor Necrosis Factor (immunology)
• Tumor Necrosis Factor-alpha (biosynthesis)