Interleukin 10 (IL-10) upregulates IL-1 receptor antagonist production from lipopolysaccharide-stimulated human polymorphonuclear leukocytes by delaying mRNA degradation.

Abstract

SummaryPolymorphonuclear leukocytes (PMN) have been identified as cells capable of producing a number of pro-and antiinflammatory cytokines in response to specific agonists. Previously, we showed that tumor necrosis factor (TNF), interleukin-lB (IL-I~, and IL-8, are produced by PMN after stimulation with agonists, such as lipopolysaccharide (LPS). In this study, we demonstrate that LPS is also a potent stimulus for the mRNA expression and release of the IL-1 receptor antagonist (IL-lra). In addition, we show that the release of IL-lra from LPS-stimulated PMN is markedly potentiated in the presence of IL-10 (from two to threefold after 18 h of stimulation). Moreover, we observed that this upregulation of IL-lra production by IL-10 in LPS-stimulated PMN took place through IL-lra mRNA stabilization. Indeed, the half-life of IL-lra mRNA was prolonged in PMN stimulated in the presence of IL-10 and LPS, as compared with cells stimulated with LPS alone. That IL-10 selectively upregulates IL-lra production in LPS-activated PMN, while it inhibits the production of IL-13, TNF, and IL-8 under the same conditions, suggests that IL-10 may be an important physiologic regulator of cytokine production from PMN, and emphasizes the potential role of IL-IO in inflammatory responses.

Lipopolysaccharide primes neutrophils for a rapid response to IL-10

“…At increasing intervals thereafter, the cultures were processed for Northern blot analysis, and the changes in the amount of TNF-a, CXCL8/IL-8 and IL-1ra mRNA were quantitated by InstantImager scanning. Under these conditions, only the half-life of IL-1ra mRNA was significantly prolonged by the addition of IL-10 (165AE23 min in LPS-treated neutrophils versus 630AE40 min in LPS + IL-10-treated neutrophils, n=3), in accordance with previous data obtained in "time 0" neutrophils costimulated with IL-10 and LPS for 5 h [20], whereas the half-lives of TNF-a and CXCL8/ IL-8 mRNA remained unchanged. 6.…”

“…Total RNA was extracted at the 90-, 210-and 300-min time points to follow the expression kinetics of the various LPS-inducible genes by Northern blot analysis. In line with previous results [9,20,[35][36][37], Fig. 5A shows that in "time 0" neutrophils, the accumulation of TNF-a, CXCL8/IL-8 and IL-1ra mRNAs in response to LPS peaks at around 90 min of stimulation and declines thereafter.…”

“…1A confirms that a pretreatment of freshly purified PBMC and autologous neutrophils (from now on referred to as "time 0" neutrophils/PBMC) with IL-10 prior to LPS stimulation only has a notable modulatory effect in PBMC with respect to TNF-a, IL-1 receptor antagonist (IL-1ra) and CXCL8/IL-8 mRNA expression at early stimulation times (90 min). By contrast, a similar modulation by IL-10 of LPS-induced TNF-a, IL-1ra and CXCL8/IL-8 gene expression in "time 0" neutrophils is only detectable after at least 4 h of culture [16,18,20,21]. In this regard, we have recently shown that the delayed effect of IL-10 in "time 0" neutrophils might reflect the necessity to synthesize IL-10R1 de novo, a process that requires 3-4 h at least [10].…”

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

“…These effects were efficiently blocked by anti-TGFβ antibodies, thus confirming the central role for TGFβ in this process [53]. IL-10, another relevant immunomodulatory cytokine produced under physiological conditions in the intestinal lamina propria, might also influence the functional properties of intestinal macrophages either by directly dampening monocyte/macrophage functions or indirectly by upregulating TGFβ production in distinct cell types, including immature DCs and macrophages [61][62][63]. Intriguingly, monocytes cultured in the presence of recombinant TGFβ alone or together with IL-10 did not gain an intestinal macrophages-like phenotype such as absence of CD14, whereas IL-10 and TGFβ synergistically downregulate CD89 and TREM-1 surface expression on blood monocytes and prevented the upregulation of these markers by proinflammatory stimuli such as LPS or TNF [54].…”

A Role for Parasite-Induced PGE2 in IL-10-Mediated Host Immunoregulation by Skin Stage Schistosomula ofSchistosoma mansoni

“…Cytokine analysis in the skin following infection with S. mansoni showed a significant reduction in the levels of IL-1␣ and IL-1␤, whereas the levels of IL-1ra were substantially increased (21). IL-10 has been shown to inhibit IL-1␣ and IL-1␤ (18,19) and to up-regulate production of IL-1ra (31). Therefore, PGE 2 -driven IL-10 production in the skin following infection may play a significant role in the immunomodulation of inflammatory responses in the skin of infected animals.…”