lnterleukin-10 Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor and Interleukin-1β Production in the Brain without Affecting the Activation of the Hypothalamus-Pituitary-Adrenal Axis

Abstract

Interleukin (IL) 10 inhibits endotoxin (lipopolysaccharide; LPS) induced tumor necrosis factor (TNF) production in vivo and in vitro. In turn, IL-10 is induced by LPS and acts as a negative feedback to limit TNF production. We investigated the effects of IL-10 on brain TNF and IL-1β production induced by a central LPS administration in mice. Because central LPS also induces peripheral TNF, we also measured the serum TNF levels. A single intracere-broventricular injection of murine recombinant IL-10 (75 ng/mouse) simultaneously with LPS (2.5 µg/mouse) almost completely inhibited brain TNF production. The brain IL-1β production was also inhibited, as was the serum concentration of the acute-phase protein serum amyloid A. On the other hand, intracerebroventricular administration of an anti-IL-10 monoclonal antibody (JES5-2A5; 60 µg/mouse) potentiated brain TNF and IL-1β production. Identical results were obtained when the serum TNF levels were measured. IL-10 did not affect the LPS-induced increase of serum corticosterone, the main endogenous inhibitor of TNF production, or the induction of IL-6. These results indicate that LPS-induced IL-10 can act as an important endogenous inhibitor of brain TNF production and suggest an anti-inflammatory role for IL-10 in the central nervous system.

Anti-Inflammatory Cytokines: Expression and Action in the Brain

“…SOCS-3 inhibits transcription of LPS-inducing genes such as those coding for IL-1 and TNF· in monocytes [11]. This is consistent with centrally administered IL-10 inhibiting LPS-induced production of IL-1 [71] and concomitant behavioral effects [72]. Both IL-10 cytokine and its receptor mRNAs were detected in cultured murine microglia and astrocytes [73].…”

“…IL-10, administered intracerebroventricularly, attenuated the depression of social interaction caused by LPS and blocked the depression of social exploration [72]. IL-10 administered together with LPS intracerebroven-Vitkovic/Maeda/Sternberg tricularly to rats antagonized the well-known LPS-mediated stimulation of IL-1ß/TNF· expression [71] and sickness behavior [72,170]. Local application of IL-10 to the site of corticosectomy in adult mice reduced the number and hypertrophy of astrocytes, the two morphological markers of reactive astrocytosis.…”

“…together with LPS (2.5 Ìg/ mouse) blocks the increases in IL-1ß and TNF· [71]. Monoclonal anti-IL-10 antibody together with LPS potentiates the increases in IL-1ß and TNF· [71]. Intravenous IL-10 blocks the increase in LPS (i.c.v.…”

Gene Therapy for Chronic Relapsing Experimental Allergic Encephalomyelitis Using Cells Expressing a Novel Soluble p75 Dimeric TNF Receptor

“…Thus, it appears that different TNF antagonists have different immunogenic and pharmacological properties. Indeed, cellular feedback mechanisms tightly control endogenous TNF production (34,35), making it likely that the degree and timing of TNF neutralization may have important consequences on the development of either pro-or antiinflammatory events. Therefore, care must be taken in moving animal data into the clinic.…”

Central Gene Transfer of Interleukin-10 Reduces Hypothalamic Inflammation and Evidence of Heart Failure in Rats After Myocardial Infarction

“…12,13 Increasing evidence indicates that IL-10 can modulate the production and/or action of proinflammatory cytokines in the central nervous system. Intracerebroventricular or intravenous administration of an adenovirus encoding the human IL-10 gene completely inhibits brain IL-1␤ and TNF-␣ production in response to intracerebroventricular lipopolysaccharide in mice 14 and blocks lipopolysaccharide-induced behavioral effects and brain damage by downregulating the inflammatory response. 15,16 The present study sought to determine whether brain proinflammatory cytokines contribute to the progression of HF in rats following MI.…”