Interleukin‐10 controls interferon‐γ and tumor necrosis factor production during experimental endotoxemia

Abstract

Interleukin-10 (IL-10) is a potent inhibitor of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production and has been shown to protect mice from endotoxin shock. As IFN-gamma is another important mediator of LPS toxicity, we studied the effects of IL-10 on LPS-induced IFN-gamma synthesis in vitro and in vivo. First, we found that the addition of recombinant human IL-10 (rhIL-10) (10 U/ml) to human whole blood markedly suppressed LPS-induced IFN-gamma release while neutralization of endogenously synthesized IL-10 resulted in increased IFN-gamma levels. The ability of rIL-10 to inhibit LPS-induced IFN-gamma synthesis was also observed in vivo in mice. Indeed, administration of 1000 U recombinant mouse IL-10 (rmIL-10) 30 min before and 3 h after challenge of BALB/c mice with 100 micrograms LPS resulted in a threefold decrease in peak IFN-gamma serum levels. We then examined the production and the role of IL-10 during murine endotoxemia. We found that LPS injection causes the rapid release of IL-10, peak IL-10 serum levels being observed 90 min after LPS challenge. Neutralization of endogenously produced IL-10 by administration of 2 mg JES5-2A5 anti-IL-10 monoclonal antibody (mAb) 2 h before LPS challenge resulted in a marked increase in both TNF and IFN-gamma serum levels while irrelevant isotype-matched mAb had no effect. The enhanced production of inflammatory cytokines in anti-IL-10 mAb-treated mice was associated with a 60% lethality after injection of 500 micrograms LPS, while all mice pretreated with control mAb survived. We conclude that the rapid release of IL-10 during endotoxemia is a natural antiinflammatory response controlling cytokine production and LPS toxicity.

Methylprednisolone differentially regulates IL-10 and tumour necrosis factor (TNF) production during murine endotoxaemia

“…This hypothesis was tested by injecting mice with neutralizing anti-IL-10 MoAb (JES5-2A5, 2 mg) before MPDS (50 mg/kg) and LPS administration. As previously reported, no immunoreactive IL-10 could be detected in the serum of anti-IL-10-treated mice ( [18] and data not shown). Figure 3 shows that neutralization of endogenous IL-10 up-regulated TNF production in mice injected with LPS with or without MPDS (hatched bars).…”

“…As previously described [18], injection of 100 g LPS into mice resulted in the rapid release of TNF (Fig. 1a) and IL-10 ( Fig.…”

“…Neutralization of endogenous IL-10 markedly increases the production of TNF and the lethality associated with endotoxin shock and septic peritonitis [18,19]. Monocytes and macrophages represent probably an important source of IL-10 in inflammatory disorders [20][21][22].…”

The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll‐like receptor‐mediated inflammatory signals

“…The role of IL-10 in experimental sepsis remains controversial. The exogenous application of IL-10 can prevent septic shock in mice by inhibiting the synthesis of proinflammatory cytokines, while neutralizing IL-10 inhibited bacterial outgrowth in lungs and improved survival during murine pneumonitis [23,24]. Furthermore, recent studies demonstrated that sepsis is characterized by a biphasic immunological response: an initial hyperinflammatory phase, followed by a hypoinflammatory phase [25,26].…”

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

“…In vitro, IL-10 is produced by monocytes and macrophages following exposure to LPS [9], and its mechanism of action includes down-regulating the production of pro-inflammatory cytokines such as IFN-c, as well as repressing IFN-c-mediated signal transducer and activator of transcription (STAT)-1 activation through induction of the suppressor of cytokine signaling family of proteins [12]. The importance of IL-10 in controlling proinflammatory cytokine release is evidenced by studies demonstrating increased mortality among mice with neutralized or deficient IL-10 following LPS challenge [13][14][15][16].…”