Abstract
PURPOSE: 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. METHODS: 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-κB) and activator protein-1 (AP-1) in mediating cytokine/chemokine release in J774 cells was also assessed. RESULTS: In mice, plasma levels of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, interleukin (IL)-10, interferon (IFN)-γ and tumour necrosis factor-alpha (TNF-α) and peritoneal lavage fluid levels of KC, MIP-2 and TNF-α increased significantly 1 h after LPS. Only KC and MIP-2 levels increased 1 h after LTA. LPS-treated (10 μg/ml) J774 cells released MIP-2, IL-10, IFN-γ and TNF-α but not KC (24 h), whereas cells treated with 10 μg/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-κB 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. CONCLUSION: LTA and LPS, at clinically relevant concentrations, induced differential cytokine/chemokine release in vitro and in vivo, via effects distal to activation of NF-κB/AP-1 that might include chromatin remodelling or mRNA stability.