Cold physical plasma-derived ROS inactivate cells, which might be beneficial in oncology. However, several aspects of plasma oncotherapy remain elusive. These include the identification of a ROS composition with maximum toxicity and the molecular mechanisms that govern the degree of plasmainduced cell death. Using two human leukemia cell lines and the plasma jet kINPen, we identified Jurkat cells to be most sensitive to argon plasma while THP-1 cells were most sensitive to He/O2 plasma. Screening of 20 protein transcripts involved in redox regulation identified HMOX1 as a commonly regulated element, and siRNA-mediated knockdown of the HMOX1-transcribed protein HO-1 augmented plasma-derived cell death in the two leukemia cell lines. Interestingly, knockdown of the H2O2decomposing enzyme catalase did not elevate plasma-induced cell death. By contrast, siRNA-mediated suppression of the production of the chemokine CXCL8 (IL8) markedly enhanced plasmaderived cytotoxicity up to twofold. Vice versa, by antibodymediated blocking of IL8 receptors, a massive increase in IL8 and HO-1 secretion was observed, together with a dramatically enhanced cell death in response to plasma treatment, especially in THP-1 cells. These results suggest that the plasma-induced leukemia cell death is dictated by the ROS chemistry and the HO-1/CXCL8 axis via paracrine or autocrine IL8-mediated prosurvival signaling.
Postoperative peritonitis is characterized by a more severe clinical course than other forms of secondary peritonitis. The pathophysiological mechanisms behind this phenomenon are incompletely understood. This study used an innovative model to investigate these mechanisms, combining the models of murine Colon Ascendens Stent Peritonitis (CASP) and Surgically induced Immune Dysfunction (SID). Moreover, the influence of the previously described anti-inflammatory reflex transmitted by the vagal nerve was characterized. SID alone, or 3 days before CASP were performed in female C57BL/6 N mice. Subdiaphragmatic vagotomy was performed six days before SID with following CASP. The immune status was assessed by FACS analysis and measurement of cytokines. Local intestinal inflammatory changes were characterized by immunohistochemistry. Mortality was increased in CASP animals previously subjected to SID. Subclinical bacteremia occurred after SID, and an immunosuppressive milieu occurred secondary to SID just before the induction of CASP. Previous SID modified the pattern of intestinal inflammation induced by CASP. Subdiaphragmatic vagotomy had no influence on sepsis mortality in our model of postoperative peritonitis. Our results indicate a surgery-induced inflammation of the small intestine and the peritoneal cavity with bacterial translocation, which led to immune dysfunction and consequently to a more severe peritonitis.
IntroductionSplenic B cells exhibit a high expression of the G protein-coupled sphingosine-1-phosphate (S1P) receptor type 4 (S1PR4). Little is known about the functional relevance of S1PR4 expression on those cells.MethodsIn this study, S1PR4-deficient mice were used to study the role of S1PR4-mediated S1P signaling in B cell motility in vitro and for the maintenance of the splenic architecture under steady state conditions as well as in polymicrobial abdominal sepsis in vivo. Finally, the impact of S1PR4 deficiency on antibody production after immunization with T cell dependent antigens was assessed.ResultsLoss of S1PR4 resulted in minor alterations of the splenic architecture concerning the presence of B cell follicles. After sepsis induction, the germinal center response was severely impaired in S1PR4-deficient animals. Splenic B cells showed reduced motility in the absence of S1PR4. However, titres of specific antibodies showed only minor reductions in S1PR4-deficient animals.DiscussionThese observations suggest that S1P signaling mediated by S1PR4 modifies chemokine-induced splenic B cell chemotaxis, thus modulating splenic microarchitecture, GC formation and T-cell dependent antibody production.
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