Inhibition of transcription factor NFAT activity in activated platelets enhances their aggregation and exacerbates gram-negative bacterial septicemia

Immunity ◽  
2022 ◽  
Author(s):  
Valentina Poli ◽  
Marco Di Gioia ◽  
Martha Sola-Visner ◽  
Francesca Granucci ◽  
Andrew L. Frelinger ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gram Negative ◽  
Activated Platelets ◽  
Transcription Factor Nfat

scholarly journals Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Yun Cai ◽  
Xiou Cao ◽  
Alejandro Aballay
Keyword(s):  
Transcription Factor ◽  
Immune Responses ◽  
Immune Activation ◽  
Bacterial Infections ◽  
Mitogen Activated Protein Kinase ◽  
Resistant Bacteria ◽  
Long Term Outcome ◽  
Gram Negative ◽  
Content Type ◽  
Chemical Screen

ABSTRACTThe purpose of this study was to take advantage of the nematodeCaenorhabditis elegansto perform a whole-animal chemical screen to identify potential immune activators that may confer protection against bacterial infections. We identified 45 marketed drugs, out of 1,120 studied compounds, that are capable of activating a conserved p38/PMK-1 mitogen-activated protein kinase pathway required for innate immunity. One of these drugs, the last-resort antibiotic colistin, protected against infections by the Gram-negative pathogensYersinia pestisandPseudomonas aeruginosabut not by the Gram-positive pathogensEnterococcus faecalisandStaphylococcus aureus. Protection was independent of the antibacterial activity of colistin, since the drug was administered prophylactically prior to the infections and it was also effective against antibiotic-resistant bacteria. Immune activation by colistin is mediated not only by the p38/PMK-1 pathway but also by the conserved FOXO transcription factor DAF-16 and the transcription factor SKN-1. Furthermore, p38/PMK-1 was found to be required in the intestine for immune activation by colistin. Enhanced p38/PMK-1-mediated immune responses by colistin did not reduce the bacterial burden, indicating that the pathway plays a role in the development of host tolerance to infections by Gram-negative bacteria.IMPORTANCEThe innate immune system represents the front line of our defenses against invading microorganisms. Given the ever-increasing resistance to antibiotics developed by bacterial pathogens, the possibility of boosting immune defenses represents an interesting, complementary approach to conventional antibiotic treatments. Here we report that the antibiotic colistin can protect against infections by a mechanism that is independent of its microbicidal activity. Prophylactic treatment with colistin activates a conserved p38/PMK-1 pathway in the intestine that helps the host better tolerate a bacterial infection. Since p38/PMK-1-mediated immune responses appear to be conserved from plants to mammals, colistin may also activate immunity in higher organisms, including humans. Antibiotics with immunomodulatory properties have the potential of improving the long-term outcome of patients with chronic infectious diseases.

scholarly journals Is the Antiproteinuric Effect of Cyclosporine A Independent of Its Immunosuppressive Function in T Cells?

2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Bin Zhang ◽  
Wei Shi
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Cyclosporine A ◽  
Immunosuppressive Effect ◽  
Molecular Event ◽  
Podocyte Injury ◽  
Antiproteinuric Effect ◽  
Nfat Activation ◽  
Per Se ◽  
Transcription Factor Nfat

The antiproteinuric effect of cyclosporine A(CsA) has been believed to result from its immunosuppressive effect on the transcription factor NFAT in T cells. However, current evidences supporting this hypothesis are missing. A recent study showed that CsA has a direct antiproteinuric effect on podocytes, suggesting a novel non-immunosuppressive mechanism for CsA's antiproteinuric effect. Conditional NFATc1 activation in podoyctes per se is sufficient to induce proteinuria in mice, indicating that NFAT activation in podocytes is a critical pathogenic molecular event leading to podocyte injury and proteinuria. Meanwhile, evidence showed that TRPC6-mediated Ca2+influx stimulates NFAT-dependent TRPC6 expression. Altogether, these advances in podocyte research indicate that calcineurin-NFAT signal or calcineurin-synaptopodin axis has a direct proteinuric effect on podocytes which raises the possibility of developing specific antiproteinuric drugs that lack the unwanted effects of calcineurin or NFAT inhibition.

scholarly journals Akt Blocks Breast Cancer Cell Motility and Invasion through the Transcription Factor NFAT

2006 ◽  
Vol 22 (1) ◽  
pp. 145
Author(s):  
Merav Yoeli-Lerner ◽  
Gary K. Yiu ◽  
Isaac Rabinovitz ◽  
Peter Erhardt ◽  
Sebastien Jauliac ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cell Motility ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Motility ◽  
Transcription Factor Nfat

scholarly journals The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease

2011 ◽  
Vol 12 (11) ◽  
pp. 1063-1070 ◽  
Author(s):  
Zhihua Liu ◽  
Jinwoo Lee ◽  
Scott Krummey ◽  
Wei Lu ◽  
Huaibin Cai ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Transcription Factor ◽  
Bowel Disease ◽  
Inflammatory Bowel ◽  
Transcription Factor Nfat

Myeloid Transcription Factor C/EBPɛ Is Involved in the Positive Regulation of Lactoferrin Gene Expression in Neutrophils

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3141-3150 ◽  
Author(s):  
Walter Verbeek ◽  
Julie Lekstrom-Himes ◽  
Dorothy J. Park ◽  
Pham My-Chan Dang ◽  
Peter T. Vuong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Bone Marrow Cells ◽  
Granulocytic Differentiation ◽  
Direct Role ◽  
Gram Negative ◽  
Protein Levels ◽  
Factor C ◽  
Marrow Cells

Abstract Targeted mutation of the myeloid transcription factor C/EBPɛ in mice results in gram-negative septic death at 3 to 5 months of age. This study defines the underlying molecular defects in their terminal granulocytic differentiation. The mRNA for the precursor protein of the cathelin-related antimicrobial peptides was almost completely absent in the bone marrow cells of C/EBPɛ−/− mice. This finding may help explain their susceptibility to gram-negative sepsis, because both are bacteriocidal peptides with potent activity against gram-negative bacteria. Superoxide production was found to be reduced in both granulocytes and monocytes of C/EBPɛ−/− mice. While gp91 phox protein levels were normal, p47phox protein levels were considerably reduced in C/EBPɛ −/− granulocytes/monocytes, possibly limiting the assembly of the NADPH oxidase. In addition, expression of mRNA of the secondary and tertiary granule proteins, lactoferrin and gelatinase, were not detected, and levels of neutrophil collagenase mRNA were reduced in bone marrow cells of the knock-out mice. The murine lactoferrin promoter has a putative C/EBP site close to the transcription start site. C/EBPɛ bound to this site in electromobility shift assay studies and mutation of this site abrogated binding to it. A mutation in the C/EBP site reduced the activity of the promoter by 35%. Furthermore, overexpression of C/EBPɛ in U937 cells increased the activity of the wild-type lactoferrin promoter by 3-fold. In summary, our data implicate C/EBPɛ as a critical factor of host antimicrobial defense and suggests that it has a direct role as a positive regulator of expression of lactoferrin in vivo.

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