Abstract
Lipopolysaccharide (LPS) induces platelet activation and enhances platelet sensitivity to aggregation, which might alter platelet counts. We found that serial doses of micro-concentration LPS significantly increased the platelet count in mice treated with kanamycin, along with increased expression of IL-6 compared with IL-3 and TPO in megakaryocytes obtained from the mouse bone morrow following LPS administration. Furthermore, LPS at lower levels ranging plus IL-6 effectively stimulated CFU-MK formation and increased CD41 expression and megakaryocyte polyploidization. Meanwhile, there was a sustained rise in the percentage of reticulated platelets in the whole blood in response to low-dosage LPS combined with IL-6. In vivo experiments also demonstrated that the administration of LPS combined with IL-6 substantially enhanced the number of circulating platelets in normal and thrombocytopenic mice. Notably, the optimal LPS concentration in combination with IL-6 might be a novel stimulator of TLR4 and IL-6R expression in Dami cell lines, which initially occurs through TLR4-IL-6R crosstalk and then involves the activation of NF-κB and phosphorylation of p38 MAPK. These data suggest a new paradigm for the regulation of megakaryocytopoiesis and platelet production via a synergistic effect of LPS and IL-6, which has the potential to be used for the design of new therapies.
Highlights
Mammals, including humans, are often in contact with Gram-negative bacteria and bacterial lipopolysaccharide (LPS)
We considered that megakaryocytes may be further influenced by pro-inflammatory cytokines from either autocrine or paracrine signaling and later differentiate into reticulated platelets (RPs) as the megakaryocytes become more susceptible to LPS due to increased TLR4 expression
To investigate the possibility that platelet production could be stimulated by the possible synergistic effect of IL-6 and micro-concentration LPS, we examined the megakaryocyte colony forming units (CFU-MK), megakaryocyte CD41 expression, polyploidization and percentages of RPs following LPS and IL-6 treatment
Summary
Effects of LPS on peripheral blood cells. To eliminate LPS release from Gram-negative microbes in the gastrointestinal tract and simulate an endogenous LPS effect, Balb/c mice were irrigated with kanamycin and injected IP with different concentrations of LPS for 10 d. The number of circulating platelets decreased at 24 h post-LPS injection compared with the control group (P < 0.05) (Fig. 1B), suggesting that platelet production occurs in response to the long-term effects of LPS plus IL-6. Significant difference of platelet counts between different treatments was revealed by MNOVA (P < 0 .01), showing as the platelet counts of mice treated by LPS and Kana plus LPS significantly higher than those of Kanamycin treatment and control group. Significant difference of platelet counts between different treatments was revealed by MNOVA (P < 0 .01), showing as the platelet counts of mice treated by LPS plus IL-6 and IL-6 significantly higher than those of 5-FU treatment and control group
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