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Differences in lipopolysaccharide- and lipoteichoic acid-induced cytokine/chemokine expression.

ABSTRACT: To investigate differences in cytokine/chemokine release in response to lipoteichoic acid (LTA) or lipopolysaccharide (LPS) and contributing cellular mechanisms, in order to improve understanding of the pathogenesis of sepsis.Levels of cytokines/chemokines were measured in plasma and peritoneal lavage fluid of 10-week-old male mice (C57/B16) following intraperitoneal injection of LTA or LPS (250 µg), and in supernatants of murine J774.2 cells, immortalised blood monocytes, or isolated human monocytes treated with LTA or LPS (0-10 µg/ml). The role of cytokine/chemokine messenger RNA (mRNA) stability versus nuclear factor-kappaB (NF-?B) and activator protein-1 (AP-1) in mediating cytokine/chemokine release in J774 cells was also assessed.In mice, plasma levels of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, interleukin (IL)-10, interferon (IFN)-? and tumour necrosis factor-alpha (TNF-?) and peritoneal lavage fluid levels of KC, MIP-2 and TNF-? increased significantly 1 h after LPS. Only KC and MIP-2 levels increased 1 h after LTA. LPS-treated (10 ?g/ml) J774 cells released MIP-2, IL-10, IFN-? and TNF-? but not KC (24 h), whereas cells treated with 10 ?g/ml LTA released only MIP-2. LPS-stimulated human monocytes released IL-10 and IL-8 (24 h); by contrast, LTA-treated cells released only IL-8. LPS and LTA activated NF-?B and AP-1 in J774 cells. The protein synthesis inhibitor cycloheximide abolished LPS-induced IL-10 mRNA expression and increased LTA- and LPS-induced mRNA for MIP-2 in J774 cells.LTA and LPS, at clinically relevant concentrations, induced differential cytokine/chemokine release in vitro and in vivo, via effects distal to activation of NF-?B/AP-1 that might include chromatin remodelling or mRNA stability.

SUBMITTER: Finney SJ

PROVIDER: S-EPMC3264860 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Differences in lipopolysaccharide- and lipoteichoic acid-induced cytokine/chemokine expression.

Finney Simon J SJ Leaver Susannah K SK Evans Timothy W TW Burke-Gaffney Anne A

Intensive care medicine 20111220 2

<h4>Purpose</h4>To investigate differences in cytokine/chemokine release in response to lipoteichoic acid (LTA) or lipopolysaccharide (LPS) and contributing cellular mechanisms, in order to improve understanding of the pathogenesis of sepsis.<h4>Methods</h4>Levels of cytokines/chemokines were measured in plasma and peritoneal lavage fluid of 10-week-old male mice (C57/B16) following intraperitoneal injection of LTA or LPS (250 µg), and in supernatants of murine J774.2 cells, immortalised blood m ...[more]

PMID: 22183712

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Project description:Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PM?) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PM? or bone marrow-derived macrophages (BMM?) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8-/-) and wild-type (WT) mice. We found that CCR8-/- PM? demonstrated attenuated secretion of tumor necrosis factor (TNF)-?, interleukin (IL)-6, and IL-10 when stimulated with lipopolysaccharide (LPS). In particular, LPS-induced IL-10 production absolutely required CCR8. CCR8-dependent cytokine secretion was characteristic of PM? but not BMM?. To further investigate this result, we selected the small molecule compound R243 from a library of compounds with CCR8-antagonistic effects on CCL1-induced Ca2+ flux and CCL1-driven PM? aggregation. Similar to CCR8-/- PM?, R243 attenuated secretion of TNF-?, IL-6, and most strikingly IL-10 from WT PM?, but not BMM?. CCR8-/- PM? and R243-treated WT PM? both showed suppressed c-jun N-terminal kinase activity and nuclear factor-?B signaling after LPS treatment when compared with WT PM?. A c-Jun signaling pathway inhibitor also produced an inhibitory effect on LPS-induced cytokine secretion that was similar to that of CCR8 deficiency or R243 treatment. As seen in CCR8-/- mice, administration of R243 attenuated peritoneal adhesions in vivo. R243 also prevented hapten-induced colitis. These results are indicative of cross talk between signaling pathways downstream of CCR8 and TLR-4 that induces cytokine production by PM?. Through use of CCR8-/- mice and the new CCR8 inhibitor, R243, we identified a novel macrophage innate immune response pathway that involves a chemokine receptor.

Dataset Information

Differences in lipopolysaccharide- and lipoteichoic acid-induced cytokine/chemokine expression.

Publications

Differences in lipopolysaccharide- and lipoteichoic acid-induced cytokine/chemokine expression.

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