Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice

Quinton, Lee J.; Blahna, Matthew T.; Jones, Matthew R.; Allen, Eri; Ferrari, Joseph D.; Hilliard, Kristie L.; Zhang, Xiaoling; Sabharwal, Vishakha; Algül, Hana; Akira, Shizuo; Schmid, Roland M.; Pelton, Stephen I.; Spira, Avrum; Mizgerd, Joseph P.

doi:10.1172/jci59408

Cited by 75 publications

(105 citation statements)

References 20 publications

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“…It is worthy to note that the NFAT, NF-kB, and STAT3 pathways shown in this study to be regulated by RCAN1 are universally important during respiratory tract infections and have been extensively studied during Pneumococcus infection (64)(65)(66). Thus, it is likely that the phenotype observed in RCAN1-deficient animals may not be specific to P. aeruginosa infection.…”

Section: Discussionmentioning

confidence: 84%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

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Respiratory tract infection with Pseudomonas aeruginosa is a common cause of hospitalization in immune-compromised individuals. However, the molecular mechanisms involved in the immune response to P. aeruginosa lung infection remain incompletely defined. In this study, we demonstrate that the regulator of calcineurin 1 (RCAN1) is a central negative regulator of inflammation in a mouse model of acute bacterial pneumonia using the opportunistic bacterial pathogen P. aeruginosa. RCAN1-deficient mice display greatly increased mortality following P. aeruginosa lung infection despite enhanced neutrophil recruitment and bacterial clearance. This mortality is associated with higher systemic levels of proinflammatory cytokines in RCAN1-deficient animals. These aberrant inflammatory responses coincide with increased transcriptional activity of proinflammatory RCAN1-target proteins NFAT and NF-κB. In addition, we reveal a novel regulatory role for RCAN1 in the ERK/STAT3 pathway both in vitro and in vivo, suggesting that aberrant STAT3 activity may significantly contribute to delayed resolution of inflammatory responses in our model. Together, these findings demonstrate that RCAN1 is a potent negative regulator of inflammation during respiratory tract infections.

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Section: Discussionmentioning

confidence: 84%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

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“…In the pancreas, we found a number of increased proinflammatory cytokines and chemokines, some of which have been validated by other studies as STAT3 target genes; moreover, high expression of proinflammatory cytokines and chemokines was found to correlate with AP severity in animal models as well as in humans. Indeed, the neutrophil chemoattractant chemokine CXCL1, which is involved in monocyte/granulocyte traffic across endo-and epithelial barriers (26,43,44), was highly upregulated during SAP. Our genetic data suggest that IL-6 trans-signalinginduced STAT3 phosphorylation in the pancreas acts as an amplifier for CXCL1 induction.…”

Section: Discussionmentioning

confidence: 99%

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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“…We observed a positive correlation between STAT3 activation and increased KIM-1 expression after ATI and in renal cell carcinoma. Only 50% of the pSTAT3-positive cells exhibit KIM-1 staining, which may be because STAT3 (being an acute phase response protein 44 ) is expressed by injured, dedifferentiating, proliferating, and dying cells, whereas only dedifferentiating and surviving cells express KIM-1. 6 Using in vivo and in vitro promoter binding assays, we were able to show that STAT3 binds to the KIM-1 promoter and regulates its transcription.…”

Section: Discussionmentioning

confidence: 99%

A Bioinformatics Approach Identifies Signal Transducer and Activator of Transcription-3 and Checkpoint Kinase 1 as Upstream Regulators of Kidney Injury Molecule-1 after Kidney Injury

Ajay

Kim

Ramírez‐González

et al. 2014

Journal of the American Society of Nephrology

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Kidney injury molecule-1 (KIM-1)/T cell Ig and mucin domain-containing protein-1 (TIM-1) is upregulated more than other proteins after AKI, and it is highly expressed in renal damage of various etiologies. In this capacity, KIM-1/TIM-1 acts as a phosphatidylserine receptor on the surface of injured proximal tubular epithelial cells, mediating phagocytosis of apoptotic cells, and it may also act as a costimulatory molecule for immune cells. Despite recognition of KIM-1 as an important therapeutic target for kidney disease, the regulators of KIM-1 transcription in the kidney remain unknown. Using a bioinformatics approach, we identified upstream regulators of KIM-1 after AKI. In response to tubular injury in rat and human kidneys or oxidant stress in human proximal tubular epithelial cells (HPTECs), KIM-1 expression increased significantly in a manner that corresponded temporally and regionally with increased phosphorylation of checkpoint kinase 1 (Chk1) and STAT3. Both ischemic and oxidant stress resulted in a dramatic increase in reactive oxygen species that phosphorylated and activated Chk1, which subsequently bound to STAT3, phosphorylating it at S727. Furthermore, STAT3 bound to the KIM-1 promoter after ischemic and oxidant stress, and pharmacological or genetic induction of STAT3 in HPTECs increased KIM-1 mRNA and protein levels. Conversely, inhibition of STAT3 using siRNAs or dominant negative mutants reduced KIM-1 expression in a kidney cancer cell line (769-P) that expresses high basal levels of KIM-1. These observations highlight Chk1 and STAT3 as critical upstream regulators of KIM-1 expression after AKI and may suggest novel approaches for therapeutic intervention.

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Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice

Cited by 75 publications

References 20 publications

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

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

A Bioinformatics Approach Identifies Signal Transducer and Activator of Transcription-3 and Checkpoint Kinase 1 as Upstream Regulators of Kidney Injury Molecule-1 after Kidney Injury

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