Toxin-induced RhoA Activity Mediates CCL1-triggered Signal Transducers and Activators of Transcription Protein Signaling

Reipschläger, Simone; Kubatzky, Katharina F.; Taromi, Sanaz; Burger, Meike; Orth, J.; Aktories, Klaus; Schmidt, Gudula

doi:10.1074/jbc.m111.313395

Cited by 13 publications

(13 citation statements)

References 39 publications

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“…Moreover, we found that the effects on the liver and kidney were only transient (Supplemental Figure 1, F-J). This model of pancreatitis-associated lung injury revealed activation of the signaling pathways IκB/NF-κB, p38, and RhoA (Supplemental Figure 2, A and B), which are known to be important for mediating damage in the lung (18,19).…”

Section: A Model For Sap-induced Lethal Alimentioning

confidence: 97%

“…Because IL-6R is only minimally expressed (mainly on hepatocytes and leukocytes), IL-6 trans-signaling dramatically increases the number of potential IL-6 target cells (16). The complexes involve the downstream kinase Jak-2 in order to phosphorylate the transcription factor STAT3 at Y705 (18,19). Tyrosine phosphorylation of Y705 is required for formation of homodimers and subsequent nuclear translocations.…”

Section: Introductionmentioning

confidence: 99%

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IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality

et al. 2013

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Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis-associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI. IntroductionAcute pancreatitis (AP) accounts for more than 220,000 hospital admissions in the United States each year. Risk factors for AP include gallstones and excessive alcohol use. Interestingly, 70%-80% of AP patients develop mild and uncomplicated AP, while 20%-30% will develop more severe symptoms with concomitant multiple organ failure (MOF) (1). MOF is a consequence of the systemic activation of the immune system, known as systemic inflammatory response syndrome (SIRS). The clinical and pathological features of SIRS mimic those of sepsis; however, efforts to identify any infecting organisms in many patients with SIRS have failed (2-4). Although this syndrome is typically seen in individuals with sepsis, SIRS also occurs in patients with severe AP (SAP), blunt trauma, aseptic burns, and widespread surgical manipulations (5, 6). A major complication during SAP is acute lung injury (ALI). Nevertheless, the clinical course of ALI in SAP is still unpredictable and has a mortality rate of up to 50%. Current therapeutic approaches in SAP and associated ALI are symptomatically based (1, 7).The pathophysiology of SAP with ALI is poorly understood. Researchers have long hypothesized that SAP results from activation of digestive enzymes within the pancreas, a process called autodigestion (8). Indeed, inherited mutations in genes encoding for digestive enzymes have been found in patients with a hereditary form of pancreatitis. However, all these patients develop chronic pancreatitis, rather than SAP with ALI (9, 10). Therefore,

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Section: A Model For Sap-induced Lethal Alimentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality

et al. 2013

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“…All data are given as mean ± SD (n ≥ 3) and significance was tested by using the Student's t-test (*P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant). triggers a negative feedback mechanism resulting in blockade of the activity state of Rho (Reipschläger et al, 2012;Augspach et al, 2013). As shown by the immunoblots, this effect was apparently not caused by degradation of Rho.…”

Section: Discussionmentioning

confidence: 68%

“…In contrast, activation of Rho by PTC5 was maximal after 4 h and remained increased for at least 18 h. Interestingly, the transient effect of CNF1 was dominant in the presence of both toxins. This finding supports our previous hypothesis that CNF1‐induced activation of Rho subfamily proteins triggers a negative feedback mechanism resulting in blockade of the activity state of Rho (Reipschläger et al ., ; Augspach et al ., ). As shown by the immunoblots, this effect was apparently not caused by degradation of Rho.…”

Section: Discussionmentioning

confidence: 99%

“…After dialysis, the protein solution was centrifuged at 20 000× g and the refolded protein solution was adjusted to a final concentration of 40% glycerol and stored at −80°C. Rho GTPases and CNF1 were expressed in E. coli BL21 (DE3) as recombinant glutathione S-transferase fusion proteins and purified by affinity chromatography with glutathione-Sepharose 4B according to the manufacturer's instructions (Guttenberg et al, 2012;Reipschläger et al, 2012). The proteins were eluted as GSTfusion proteins with buffer containing 50 mM Tris-HCl, pH 8.0 and 10 mM reduced glutathione.…”

Section: Protein Expression and Purificationmentioning

confidence: 99%

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The actin and Rho-modifying toxins PTC3 and PTC5 ofPhotorhabdus luminescens: enzyme characterization and induction of MAL/SRF-dependent transcription

et al. 2014

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Obesity causes PGC‐1α deficiency in the pancreas leading to marked IL‐6 upregulation via NF‐κB in acute pancreatitis

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et al. 2018

The Journal of Pathology

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Obesity is associated with local and systemic complications in acute pancreatitis. PPARγ co-activator 1α (PGC-1α) is a transcriptional co-activator and master regulator of mitochondrial biogenesis that exhibits dysregulation in obese subjects. Our aims were 1) to study PGC-1α levels in pancreas from lean or obese rats and mice with acute pancreatitis; and 2) to determine the role of PGC-1α in the inflammatory response during acute pancreatitis elucidating the signaling pathways regulated by PGC-1α. Lean and obese Zucker rats and lean and obese C57BL6 mice were used first, and subsequently wild-type and PGC-1α knock-out (KO) mice with cerulein-induced pancreatitis were used to assess the inflammatory response and expression of target genes. Ppargc1a mRNA and protein levels were markedly down-regulated in pancreas of obese mice versus lean mice. PGC-1α protein levels increased in pancreas of lean mice with acute pancreatitis, but not in obese mice with pancreatitis. Il6 mRNA levels were dramatically up-regulated in pancreas of PGC-1α KO mice after cerulein-induced pancreatitis in comparison with wild type mice with pancreatitis. Edema and the inflammatory infiltrate were more intense in pancreas from PGC-1α KO mice than in wild type mice. The lack of PGC-1α markedly enhanced nuclear translocation of phospho-p65 and recruitment of p65 to Il6 promoter. PGC-1α bound phospho-p65 in pancreas during pancreatitis in wild type mice. Glutathione depletion in cerulein-induced pancreatitis was more severe in KO mice than in wild type mice. PGC-1α KO mice with pancreatitis, but not wild type mice, exhibited increased MPO activity in the lungs together with alveolar wall thickening and collapse, which were abrogated by blockade of the IL-6 receptor gp130 with LMT-28. In conclusion, obese rodents exhibit PGC-1α deficiency in the pancreas. PGC-1α acts as selective repressor of NF-κB towards IL-6 in pancreas. PGC-1α deficiency markedly enhanced NF-κB-mediated up-regulation of Il6 in pancreas in pancreatitis, leading to severe inflammatory response.

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Toxin-induced RhoA Activity Mediates CCL1-triggered Signal Transducers and Activators of Transcription Protein Signaling

Cited by 13 publications

References 39 publications

IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality

IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality

The actin and Rho-modifying toxins PTC3 and PTC5 ofPhotorhabdus luminescens: enzyme characterization and induction of MAL/SRF-dependent transcription

Obesity causes PGC‐1α deficiency in the pancreas leading to marked IL‐6 upregulation via NF‐κB in acute pancreatitis

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