Altered eosinophil profile in mice with ST6Gal-1 deficiency: an additional role for ST6Gal-1 generated by the P1 promoter in regulating allergic inflammation

Nasirikenari, Mehrab; Chandrasekaran, E. V.; Matta, Khushi L.; Segal, Brahm H.; Bogner, Paul N.; Lugade, Amit A.; Thanavala, Yasmin; Lee, James J.; Lau, Joseph T.Y.

doi:10.1189/jlb.1108704

Cited by 42 publications

(57 citation statements)

References 49 publications

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“…At baseline, the Siat1⌬P1 mouse was normal in all respects, with nominal alterations to circulatory blood counts, normal clotting times, cytokines, and major inflammatory proteins (see supplemental data). However, upon challenge with pro-inflammatory stimuli, the Siat1⌬P1 mouse responded with overly robust neutrophilic and eosinophilic inflammatory responses that had been attributed to hyperactive myelopoiesis (22,23). Direct P1-mediated transcriptional activity in the bone marrow could not be detected, and its utilization appears to be highly restricted to the liver.…”

Section: Discussionmentioning

confidence: 94%

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Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Jones

Nasirikenari

et al. 2010

Journal of Biological Chemistry

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Recent findings have established a role for the ST6Gal-1 sialyltransferase in modulating inflammatory cell production during Th1 and Th2 responses. ST6Gal-1 synthesizes the Sia(␣2,6) to Gal(␤1,4)GlcNAc linkage on glycoproteins on cell surfaces and in systemic circulation. Engagement of P1, one of six promoter/regulatory regions driving murine ST6Gal-1 gene expression, generates the ST6Gal-1 for myelopoietic regulation. P1 utilization, however, is restricted to the liver and silent in hematopoietic cells. We considered the possibility that myelopoiesis is responsive to the sialylation of liver-derived circulatory glycoproteins, such that reduced ␣2,6-sialylation results in elevated myelopoiesis. However, 2-dimensional differential in gel electrophoresis (2D-DIGE) analysis disclosed only minimal alterations in the sialylation of sera glycoproteins of ST6Gal-1-deficient mice when compared with wild-type controls, either at baseline or during an acute phase response when the demand for sialylation is greatest. Furthermore, sera from ST6Gal-1-deficient animals did not enhance myelopoietic activity in ex vivo colony formation assays. Whereas there was only minimal consequence to the ␣2,6-sialylation of circulatory glycoproteins, ablation of the P1 promoter did result in strikingly depressed levels of ST6Gal-1 released into systemic circulation. Therefore, we considered the alternative possibility that myelopoiesis may be regulated not by the hepatic sialyl glycoproteins, but by the ST6Gal-1 that was released directly into circulation. Supporting this, ex vivo colony formation was notably attenuated upon introduction of physiologic levels of ST6Gal-1 into the culture medium. Our data support the idea that circulatory ST6Gal-1, mostly of hepatic origin, limits myelopoiesis by a mechanism independent of hepatic sialylation of serum glycoproteins.␣2,6-Sialic acid modification is a common feature of glycoproteins in systemic circulation, particularly those glycoproteins originating from the liver. The ␣2,6 attachment of sialic acid to Gal(␤1,4)GlcNAc termini of glycoproteins is mediated by the sialyltransferase ST6Gal-1. Mutant mice unable to express ST6Gal-1 are essentially devoid of ␣2,6-sialyl modifications, as evidenced by the lack of binding to the Sambucus nigra lectin (SNA) 2 that specifically recognizes these structures (1). Hepatic expression of ST6Gal-1 is principally driven by P1 (2, 3), one of six independently operative promoter regions regulating transcription of the ST6Gal-1 gene (4). Another promoter, P3, is responsible for low-level ST6Gal-1 expression in the liver (5). Increased expression of liver ST6Gal-1, mediated by the P1 promoter, has long been recognized to be an integral part of the acute phase response (APR) (6 -8), and it was generally believed that elevation of ST6Gal-1 was necessary to address the increased demand for sialylation of the acute phase proteins. The Siat1⌬P1 mouse, with a specific inactivation of P1 without compromising ST6Gal-1 gene expression from the remaining promoters, was ...

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Section: Discussionmentioning

confidence: 94%

“…poiesis, as mice with a specific ablation to the P1 region had excessive neutrophilic and eosinophilic inflammatory responses (22,23). Siat1⌬P1 animals had the identical degree of excessive inflammation as Siat1-null animals that were completely devoid of ST6Gal-1, indicating only the P1-mediated pool of ST6Gal-1 was important for myelopoietic regulation.…”

mentioning

confidence: 98%

Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Jones

Nasirikenari

et al. 2010

Journal of Biological Chemistry

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“…Because ablation of P1 results only in decreased ST6Gal-1 in the liver and systemic circulation (16,17), our observation strongly infers a role for circulatory ST6Gal-1, previously considered a functionless byproduct of metabolic inefficiency, in the construction of the sialic acid linkage on the Fc glycans. Reduced circulatory ST6Gal-1 resulting in the lack of Sia-Fc may explain the generally proinflammatory tendencies noted in the Siat1⌬P1 mouse (11).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, Siat1⌬P1 mice might lack the particular subset of B cells that produce sialylated Fc glycans. Indeed, circulatory ST6Gal-1 deficiency has been attributed to altered hematopoietic activity in bone marrow (11,12,16). IgG acquires antiinflammatory properties upon Fc sialylation.…”

Section: Discussionmentioning

confidence: 99%

“…Our laboratory has demonstrated that ST6Gal-1 deficiency results in a generally proinflammatory state; mice with genetically induced ST6Gal-1 deficiency exhibit exaggerated acute peritonitis and Th2 pulmonary inflammation (11,12). This phenotype was attributed specifically to the inactivation of the liver-specific promoter P1, one of six promoters regulating tissue-and cell-specific transcription of the ST6Gal-1 gene (13)(14)(15).…”

Section: Large-dose Intravenous Immunoglobulin (Ivig)mentioning

confidence: 99%

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Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Jones

Nasirikenari

Lugade

et al. 2012

Journal of Biological Chemistry

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Background: ␤-Galactoside ␣2,6-sialyltransferase 1 (ST6Gal-1) action is essential for the anti-inflammatory activity in intravenous immunoglobulin (IVIG) therapy. Results: Fc sialylation changes in accordance to the severity of inflammation. Inactivation of the P1 promoter abrogated IgG Fc sialylation. Conclusion: Fc sialylation depends on ST6Gal-1 in the circulation. Defective Fc sialylation is a mechanism for the generally proinflammatory tendencies of the P1-ablated mutant mouse (Siat1⌬P1). Significance: Anti-inflammatory bioactivity of IVIG requires sialylated Fc.

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Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand‐foot syndrome

Watts

Wills

Madi

et al. 2022

Intl Journal of Cancer

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Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand‐foot syndrome (HFS) or palmar‐plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type‐2 diabetes (T2D), a disease also associated with HFS. We analysed genome‐wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN‐B trials. One thousand and fifty‐five patients were treated with XELOX ± cetuximab and 745 with folinic acid, fluorouracil and oxaliplatin ± cetuximab. We also analysed rs6783836 in ST6GAL1 with HFS in CRC patients from QUASAR2. Using UK Biobank data, we sought to confirm an association between ST6GAL1 and T2D (17 384 cases, 317 887 controls) and analysed rs6783836 against markers of diabetes, inflammation and psoriasis. We found that 68% of patients from COIN and COIN‐B with grade 2‐3 HFS responded to treatment as compared to 58% with grade 0‐1 HFS (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02‐1.2, P = 2.0 × 10−4). HFS was also associated with improved overall survival (hazard ratio = 0.92, 95% CI = 0.84‐0.99, P = 4.6 × 10−2). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR = 3.1, 95% CI = 2.1‐4.6, P = 4.3 × 10−8) and was borderline significant in patients receiving capecitabine from QUASAR2, but with an opposite allele effect (OR = 0.66, 95% CI = 0.42‐1.03, P = .05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR = 0.94, 95% CI = 0.92‐0.96, P = 1.2 × 10−8) and the rs6783836‐T allele was associated with lowered HbA1c levels (P = 5.9 × 10−3) and lymphocyte count (P = 2.7 × 10−3), and psoriasis (P = 7.5 × 10−3) beyond thresholds for multiple testing. In conclusion, HFS is a biomarker of treatment outcome and rs6783836 in ST6GAL1 is a potential biomarker for HFS with links to T2D and inflammation.

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Altered eosinophil profile in mice with ST6Gal-1 deficiency: an additional role for ST6Gal-1 generated by the P1 promoter in regulating allergic inflammation

Cited by 42 publications

References 49 publications

Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand‐foot syndrome

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