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Potential Roles of Innate Immune Chemokine and Cytokine Network on Lipopolysaccharide-Based Therapeutic Approach in Ovarian Cancer.

ABSTRACT: Ovarian cancer (OC), the deadliest gynecological cancer, results in poor overall survival, urgently requiring a novel therapeutic approach. As cumulative exposures to endotoxins decreased OC risk epidemiologically, we evaluated if LPS, a Toll-like receptor 4 agonist known as active component of endotoxins, could increase survival in the murine peritoneal dissemination model of SKOV-3 OC cells. LPS significantly increased the mean survival time of more than 116 days compared with 63 days in the control. Furthermore, no tumor burden was present in three mice among eight LPS-treated mice. SKOV-3 cells were not responsive to LPS and showed unaltered chemokine signature. Rather than direct effects to OC cells, LPS was found to increase proinflammatory chemokines and cytokines, such as CXCL1, CXCL8, TNF, and IL-1B, in innate immune system. Taken together, LPS is likely to potentiate the cytotoxic-related innate immunogenicity via proinflammatory chemokines and cytokines, which attenuates the peritoneal dissemination of OC.

SUBMITTER: Ignacio RMC

PROVIDER: S-EPMC6597445 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Potential Roles of Innate Immune Chemokine and Cytokine Network on Lipopolysaccharide-Based Therapeutic Approach in Ovarian Cancer.

Ignacio Rosa Mistica C RMC Lee Eun-Sook ES Son Deok-Soo DS

Immune network 20190617 3

Ovarian cancer (OC), the deadliest gynecological cancer, results in poor overall survival, urgently requiring a novel therapeutic approach. As cumulative exposures to endotoxins decreased OC risk epidemiologically, we evaluated if LPS, a Toll-like receptor 4 agonist known as active component of endotoxins, could increase survival in the murine peritoneal dissemination model of SKOV-3 OC cells. LPS significantly increased the mean survival time of more than 116 days compared with 63 days in the c ...[more]

PMID: 31281719

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Project description:BACKGROUND:Practical methods of monitoring innate immune mucosal responsiveness are lacking. Lipopolysaccharide (LPS) is a component of the cell wall of Gram negative bacteria and a potent activator of Toll-like receptor (TLR)-4. To measure LPS responsiveness of the nasal mucosa, we administered LPS as a nasal spray and quantified chemokine and cytokine levels in mucosal lining fluid (MLF). METHODS:We performed a 5-way cross-over, single blind, placebo-controlled study in 15 healthy non-atopic subjects (n = 14 per protocol). Doses of ultrapure LPS (1, 10, 30 or 100?g/100?l) or placebo were administered by a single nasal spray to each nostril. Using the recently developed method of nasosorption with synthetic adsorptive matrices (SAM), a series of samples were taken. A panel of seven cytokines/chemokines were measured by multiplex immunoassay in MLF. mRNA for intercellular cell adhesion molecule-1 (ICAM-1) was quantified from nasal epithelial curettage samples taken before and after challenge. RESULTS:Topical nasal LPS was well tolerated, causing no symptoms and no visible changes to the nasal mucosa. LPS induced dose-related increases in MLF levels of IL-1?, IL-6, CXCL8 (IL-8) and CCL3 (MIP-1?) (AUC at 0.5 to 10h, compared to placebo, p<0.05 at 30 and 100?g LPS). At 100?g LPS, IL-10, IFN-? and TNF-? were also increased (p<0.05). Dose-related changes in mucosal ICAM-1 mRNA were also seen after challenge, and neutrophils appeared to peak in MLF at 8h. However, 2 subjects with high baseline cytokine levels showed prominent cytokine and chemokine responses to relatively low LPS doses (10?g and 30?g LPS). CONCLUSIONS:Topical nasal LPS causes dose-dependent increases in cytokines, chemokines, mRNA and cells. However, responsiveness can show unpredictable variations, possibly because baseline innate tone is affected by environmental factors. We believe that this new technique will have wide application in the study of the innate immune responses of the respiratory mucosa. KEY MESSAGES:Ultrapure LPS was used as innate immune stimulus in a human nasal challenge model, with serial sampling of nasal mucosal lining fluid (MLF) by nasosorption using a synthetic absorptive matrix (SAM), and nasal curettage of mucosal cells. A dose response could be demonstrated in terms of levels of IL-1?, IL-6, CXCL8 and CCL3 in MLF, as well as ICAM-1 mRNA in nasal curettage specimens, and levels of neutrophils in nasal lavage. Depending on higher baseline levels of inflammation, there were occasional magnified innate inflammatory responses to LPS. TRIAL REGISTRATION:Clinical Trials.gov NCT02284074.

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 (PMφ) 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 PMφ or bone marrow-derived macrophages (BMMφ) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8-/-) and wild-type (WT) mice. We found that CCR8-/- PMφ demonstrated attenuated secretion of tumor necrosis factor (TNF)-α, 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 PMφ but not BMMφ. 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 PMφ aggregation. Similar to CCR8-/- PMφ, R243 attenuated secretion of TNF-α, IL-6, and most strikingly IL-10 from WT PMφ, but not BMMφ. CCR8-/- PMφ and R243-treated WT PMφ both showed suppressed c-jun N-terminal kinase activity and nuclear factor-κB signaling after LPS treatment when compared with WT PMφ. 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 PMφ. 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

Potential Roles of Innate Immune Chemokine and Cytokine Network on Lipopolysaccharide-Based Therapeutic Approach in Ovarian Cancer.

Publications

Potential Roles of Innate Immune Chemokine and Cytokine Network on Lipopolysaccharide-Based Therapeutic Approach in Ovarian Cancer.

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