Abstract
The intestinal microflora is critical for normal development, with aberrant colonization increasing the risk for necrotizing enterocolitis (NEC). In contrast, probiotic bacteria have been shown to decrease its incidence. Multiple pro- and anti-inflammatory cytokines have been identified as markers of intestinal inflammation, both in human patients with NEC and in models of immature intestine. Specifically, IL-10 signaling attenuates intestinal responses to gut dysbiosis, and disruption of this pathway exacerbates inflammation in murine models of NEC. However, the effects of probiotics on IL-10 and its signaling pathway, remain poorly defined. Real-time PCR profiling revealed developmental regulation of MIP-2, TNF-α, IL-12, IL-10 and the IL-10R2 subunit of the IL-10 receptor in immature murine colon, while the expression of IL-6 and IL-18 was independent of postnatal age. Enteral administration of the probiotic Lactobacillus rhamnosus GG (LGG) down-regulated the expression of TNF-α and MIP-2 and yet failed to alter IL-10 mRNA and protein expression. LGG did however induce mRNA expression of the IL-10R2 subunit of the IL-10 receptor. IL-10 receptor activation has been associated with signal transducer and activator of transcription (STAT) 3-dependent induction of members of the suppressors of cytokine signaling (SOCS) family. In 2 week-old mice, LGG also induced STAT3 phosphorylation, increased colonic expression of SOCS-3, and attenuated colonic production of MIP-2 and TNF-α. These LGG-dependent changes in phosphoSTAT3, SOCS3, MIP-2 and TNF-α were all inhibited by antibody-mediated blockade of the IL-10 receptor. Thus LGG decreased baseline proinflammatory cytokine expression in the developing colon through upregulation of IL-10 receptor-mediated signaling, most likely due to the combined induction of phospho-STAT3 and SOCS3. Furthermore, LGG-dependent increases in IL-10R2 were associated with reductions in TNF-α, MIP-2 and disease severity in a murine model of intestinal injury in the immature colon.
Highlights
Exaggerated proinflammatory responses and deficient inflammatory resolution in the developing intestine are implicated in the pathogenesis of intestinal diseases such as necrotizing enterocolitis (NEC) [1,2]
We examine the effects of Lactobacillus rhamnosus GG (LGG) on both baseline cytokine levels and on cytokine signaling responses to intestinal injury in the developing murine intestine
We showed that even in the absence of exogenous inflammatory stimuli, the baseline expression of key cytokines mediating both promotion and resolution of intestinal inflammation in models of NEC-like injury are developmentally regulated during the postnatal period
Summary
Exaggerated proinflammatory responses and deficient inflammatory resolution in the developing intestine are implicated in the pathogenesis of intestinal diseases such as necrotizing enterocolitis (NEC) [1,2]. NEC has been linked to aberrant mucosal responses to bacterial colonization both in the intestine of premature infants [3,4,5] and in experimental models of NEC-like inflammation [6]. Promotion of normal colonization through the oral administration of commensal or probiotic flora has been shown to attenuate intestinal inflammation [7,8] and promote barrier in experimental models of the developing intestine [9,10] and NEC [11]. IL-10-dependent suppression of cytokine signaling could be a final common pathway protecting against these inflammatory mediators during NEC-like inflammation in the developing intestine
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