Endogenous mouse interleukin-10 is up-regulated by exogenously administered recombinant human interleukin-10, but does not contribute to the efficacy of the human protein in mouse models of endotoxemia.
In murine models of experimental endotoxemia, inflammatory cytokines as well as antiinflammatory interleukin-10 (IL-10) appear in the circulation after the injection of lipopolysaccharide (LPS). There is considerable experimental evidence to suggest that the major function of endogenously produced IL-10 is to down-regulate inflammatory cytokine production. Indeed, the protective effects of exogenously administered IL-10 against murine endotoxin lethality have been shown to correlate with its ability to inhibit the LPS-induced production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). While mouse IL-10 (mIL-10) has been used in the majority of studies in murine endotoxemia, we have found the human homolog to be equally effective in suppressing inflammatory cytokine production and in protecting mice from endotoxin lethality. However, we have recently observed that the LPS-induced endogenous IL-10 response is enhanced when mice are treated with recombinant human IL-10 (rhuIL-10). The upregulation of endogenous IL-10 by exogenously administered rhuIL-10 is particularly evident in mice that are primed with Corynebacterium partum (Proprionibacterium acnes). In the present study, we have examined the potential contributions of the increased circulating levels of mouse IL-10 to the inhibitory effects seen with rhuIL-10 on inflammatory cytokine production and endotoxin lethality. We show that pretreatment with a neutralizing anti-mouse IL-10 monoclonal antibody (mAb) has no effect on the ability of rhuIL-10 to suppress an LPS-induced inflammatory cytokine response in these mice. In contrast, the suppressive effects of the human protein on inflammatory cytokine responses are blocked completely by pretreating the animals with an anti-huIL-10 mAb. These data show that despite the up-regulated endogenous IL-10 response, it is the exogenously administered rhuIL-10 that is directly responsible for the suppressed inflammatory cytokine responses that are observed when the human protein is given to endotoxemic mice.
Smith
S R
SR
Department of Immunology, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. sidneysmith@spcorp.com
Terminelli
C
C
Denhardt
G
G
Manfra
D
D
Davies
L
L
Narula
S
S
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011425:Propionibacterium acnes; D011994:Recombinant Proteins / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
D016207:Cytokines; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016753:Interleukin-10