Aberrant monocyte prostaglandin synthase 2 (PGS2) expression in type 1 diabetes before and after disease onset

Litherland, Sally A.; She, Jin‐Xiong; Schatz, Desmond; Fuller, K.; Hutson, Alan D.; Peng, Ri‐He; Li, Y.; Grebe, Kristie M.; Whittaker, Donna S.; Bahjat, Keith S.; Hopkins, Diane; Fang, Qi; Spies, P. D.; North, Kerri; Wasserfall, Clive; Cook, Ralph W.; Dennis, M. A.; Crockett, Samuel E.; Sleasman, John W.; Kocher, Jean Pierre A.; Muir, Andrew; Silverstein, Janet H.; Atkinson, Mark A.; Clare‐Salzler, Michael

doi:10.1034/j.1399-5448.2003.00042.x

Cited by 22 publications

(32 citation statements)

References 22 publications

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“…We remained blinded to the intervention status to DPT participant intervention status throughout our studies; and therefore, treatment subgroups were not considered in our studies. No attempt was made to match samples for age or gender in this study, as these factors found were not significant in our previous studies of PGS2 expression in these populations [19][20][21]. Due to limited blood sample volume available, not all assays could be run on any one sample.…”

Section: Human Cell Samplesmentioning

confidence: 99%

“…Autoimmune (AI) subject samples were obtained during their participation in one of three clinical Type 1 diabetes trials: Diabetes Prevention Trial-1 (DPT-1), Gainesville Subcutaneous Injection Trial (SQ), and Natural History (NH) studies (IRB approved protocol #372-96, Table 1) [19][20][21]. In these trials, 'at-risk' for Type 1 diabetes was defined by production of autoantibodies (IAA+, GAD+, and/or IA-2+), family history of the disease, and/or low first phase insulin response (FPIR).…”

Section: Human Cell Samplesmentioning

confidence: 99%

“…Intracellular flow cytometric analysis of human CD14+ monocyte PGS2 expression and STAT5 phosphorylation was done as previously described [19][20][21]. For human monocyte analyses, PE-and FITC-conjugated anti-PGS2 monoclonal antibodies (Cayman Chemical, Ann Arbor, MI) were used in conjunction with FITC-conjugated anti-STAT5 polyclonal antibodies (Santa Cruz Biotech, Santa Cruz, CA) or PE-conjugated anti-STAT5 tyrosine phosphorylated specific monoclonal antibodies [anti-STAT5Ptyr, Upstate Biotech (Charlottesville, VA) conjugated with Prozyme (San Leandro, CA) PE-modification kit].…”

Section: Flow Cytometric Analysis Of Pgs2 Expression and Stat5 Phosphmentioning

confidence: 99%

“…We previously reported that unactivated monocytes from diabetic/at-risk humans aberrantly express the normally inducible cyclooxygenase, prostaglandin synthase 2 (PGS2/COX2) [19,20]. This early monocyte dysfunction seen in at-risk individuals correlates with low first phase insulin responsiveness (FPIR) and risk for diabetes [19,20].…”

Section: Introductionmentioning

confidence: 99%

“…This early monocyte dysfunction seen in at-risk individuals correlates with low first phase insulin responsiveness (FPIR) and risk for diabetes [19,20]. PGS2 overexpression, through its overproduction of prostaglandin E2 (PGE2), may promote the microenvironment favorable for chronic inflammation and immune dysregulation in at-risk and autoimmune individuals.…”

Section: Introductionmentioning

confidence: 99%

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Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages

Litherland

Xie

Grebe

et al. 2005

Journal of Autoimmunity

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Autocrine granulocyte macrophage-colony stimulating factor (GM-CSF) sequentially activates intracellular components in monocyte/macrophage production of the pro-inflammatory and immunoregulatory prostanoid, prostaglandin E2 (PGE2). GM-CSF first induces STAT5 signaling protein phosphorylation, then prostaglandin synthase 2 (COX2/PGS2) gene expression, and finally IL-10 production, to downregulate the cascade. Without activation, monocytes of at-risk, type 1 diabetic (T1D), and autoimmune thyroid disease (AITD) humans, and macrophages of nonobese diabetic (NOD) mice have aberrantly high GM-CSF, PGS2, and PGE2 expression, but normal levels of IL-10. After GM-CSF stimulation, repressor STAT5A and B isoforms (80-77 kDa) in autoimmune human and NOD monocytes and activator STAT5A (96-94 kDa) and B (94-92 kDa) isoforms in NOD macrophages stay persistently tyrosine phosphorylated. This STAT5 phosphorylation persisted despite treatment in vitro with IL-10, anti-GM-CSF antibody, or the JAK2/3 inhibitor, AG490. Phosphorylated STAT5 repressor isoforms in autoimmune monocytes had diminished DNA binding capacity on GAS sequences found in the PGS2 gene enhancer. In contrast, STAT5 activator isoforms in NOD macrophages retained their DNA binding capacity on these sites much longer than in healthy control strain macrophages. These findings suggest that STAT5 dysfunction may contribute to dysregulation of GM-CSF signaling and gene activation, including PGS2, in autoimmune monocytes and macrophages.

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Section: Human Cell Samplesmentioning

confidence: 99%

Section: Human Cell Samplesmentioning

confidence: 99%

Section: Flow Cytometric Analysis Of Pgs2 Expression and Stat5 Phosphmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages

Litherland

Xie

Grebe

et al. 2005

Journal of Autoimmunity

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Aloe Emodin Alleviates Radiation‐Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption

Ouyang,

Li,

Wang

et al. 2024

Advanced Science

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Aloe emodin is an anthraquinone of traditional Chinese medicine monomer, which plays a protective action in cardiovascular diseases. However, the regulatory mechanisms of aloe emodin in the protection of radiation‐induced heart damage (RIHD) are unclear. As a novel post‐translational modification, lactylation is considered as a critical mediator in inflammatory cascade and cardiac injury. Here, using a cross of differential omics and 4D label‐free lactylation omics, protein disulfide‐isomerase (P4HB) is identified as a novel target for lactylation, and aloe emodin inhibits the binding of lactate to the K311 site of P4HB. Aloe emodin stabilizes kynurenine metabolism through inhibition of aspartate aminotransferase (GOT2) accumulation on damaged mitochondria. Mechanistically, aloe emodin inhibits phosphorylated glycogen synthase kinase 3B (p‐GSK3B) transcription in the nucleus to repress the interaction of prostaglandin G/H synthase 2 (PTGS2) with SH3 domain of SH3 domain‐containing GRB2‐like protein B1 (SH3GLB1), thereby disrupting the functions of mitochondrial complexes and reducing SH3GLB1‐mediated mitoROS accumulation, eventually suppressing calcium‐binding and coiled‐coil domain‐containing protein 2 (NDP52)‐induced mitophagy. This study unveils the regulatory role of aloe emodin in RIHD alleviation through PTGS2/SH3GLB1/NDP52 axis, indicates aloe emodin stabilizes GOT2‐mediated kynurenine metabolism through P4HB lactylation. Collectively, this study provides novel insights into the regulatory mechanisms underlying the protective role of aloe emodin in cardiac injury, and opens new avenues for therapeutic strategies of aloe emodin in preventing RIHD by regulating lactylation.

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Prevention strategies for type 1 diabetes

Kishiyama

Chase

Barker

2006

Rev Endocr Metab Disord

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Type 1 diabetes (T1D) is a common chronic disease of childhood. Patients with T1D are at significant risk for developing serious health complications. Understanding of the genetics, environmental factors, and natural history of diabetes has lead to greater understanding of the etiology and epidemiology of T1D. Furthermore, technology has greatly improved glycemic control and reduction of complications. However, prevention of the development of diabetes remains elusive. This review article describes the past, current and upcoming strategies for diabetes prevention for patients at risk for developing autoimmunity, after antibody production, and patients with new onset diabetes.

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Aberrant monocyte prostaglandin synthase 2 (PGS2) expression in type 1 diabetes before and after disease onset

Abstract: These findings suggest that high level monocyte PGS2 expression, although subject to fluctuation, is present in at-risk subjects at an early age and is maintained during progression to and after type 1 diabetes onset.

Cited by 22 publications

References 22 publications

Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages

Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages

Aloe Emodin Alleviates Radiation‐Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption

Prevention strategies for type 1 diabetes

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