On the origin of serum CD26 and its altered concentration in cancer patients

Cordero, Oscar J.; Salgado, Francisco; Nogueira, Marco Aurélio

doi:10.1007/s00262-009-0728-1

Cited by 186 publications

(294 citation statements)

References 314 publications

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“…However, because we also observed a similar Th17 phenotype in other hepatic viral and autoimmune diseases (Fig. 5A), and soluble CD26 may be released by hepatocytes as well (40), further studies will have to clarify whether Th17 cells are indeed a major source of CD26 enzymatic activity in chronic hepatitis C virus infection.…”

Section: Discussionmentioning

confidence: 93%

Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)

Bengsch

Seigel

Flecken

et al. 2012

The Journal of Immunology

149

154

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Dipeptidylpeptidase IV (CD26) is a multifunctional ectoenzyme involved in T cell activation that has been implicated in autoimmune pathophysiology. Because IL-17–producing CD4+ T cells (Th17 cells) are important mediators of autoimmune disease, we analyzed the expression of CD26 and its enzymatic function on human Th17 cells. Analysis of CD26 expression on different CD4+ T helper subsets showed that CD26 expression is highest on CD4+ T cells producing type 17 cytokines (e.g., IL-22, IL-17, GM-CSF, or TNF) compared with Th1, Th2, and regulatory T cells. Phenotypic analysis revealed that CD26++CD4+ T cells express the type 17 differentiation molecules CD161, CCR6, lL-23R, and retinoic acid-related orphan receptor-γt. Furthermore, sorted CD26++CD4+ T cells contain >90–98% of Th17 cells, indicating that CD26++ T cells harbor the Th17 lineage. A comparison with CD161 and CCR6 indicated that analysis of CD26 coexpression may improve the phenotypic characterization of Th17 cells. Of note, CD26++ Th17 cells are enriched in the inflamed tissue of patients with hepatitis and inflammatory bowel disease. Functional analysis in migration assays revealed that CD26 expressed on Th17 cells is enzymatically active. Indeed, CD26 negatively regulates the chemotactic CD4+ T cell response to the inflammatory chemokines CXCL9–12 that can be restored by pharmacological blockade of the enzymatic center of CD26. In summary, these results strongly suggest that CD26 may contribute to the orchestration of the immune response by Th17 cells in human inflammatory diseases. They also suggest that the phenotypic analysis of Th17 cells may be facilitated by determination of CD26 expression.

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Section: Discussionmentioning

confidence: 93%

Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)

Bengsch

Seigel

Flecken

et al. 2012

The Journal of Immunology

149

154

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“…11,12 GLP-1 and GIP are target proteins of dipeptidyl peptidase-4 (DPP-4) and rapidly degraded and inactivated by this proteolytic enzyme. 13,14 Since GLP-1 and GIP augment glucose-induced insulin release from pancreatic b-cells, suppress glucagon secretion and slow gastric emptying, 11,12 inhibition of DPP-4 has been proposed as a potential therapeutic target for the treatment of patients with type 2 diabetes.…”

mentioning

confidence: 99%

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

Matsui

Nakashima

Nishino

et al. 2015

Laboratory Investigation

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Advanced glycation end products (AGEs) and their receptor (RAGE) have a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4), could inhibit renal damage in type 1 diabetic rats by suppressing the AGE-RAGE axis. However, it remains unclear whether DPP-4 deficiency could also have beneficial effects on experimental diabetic nephropathy. To address the issue, we rendered wild-type F344/NSlc and DPP-4-deficient F344/DuCrl/Crlj rats diabetic by injection of streptozotocin, and then investigated whether DPP-4 deficiency could block the activation of AGE-RAGE axis in the diabetic kidneys and resultantly ameliorate renal injury in streptozotocin-induced diabetic rats. Compared with control rats at 9 and 11 weeks old, body weight and heart rates were significantly lower, while fasting blood glucose was higher in wild-type and DPP-4-deficient diabetic rats at the same age. There was no significant difference of body weight, fasting blood glucose and lipid parameters between the two diabetic rat strains. AGEs, 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nitrotyrosine levels in the kidney, renal gene expression of RAGE and intercellular adhesion molecule-1, glomerular area, urinary excretion of 8-OHdG and albumin, and the ratio of renal to body weight were increased in wild-type diabetic rats at 9 and/or 11 weeks old compared with age-matched control rats, all of which except for urinary 8-OHdG levels at 11 weeks old were significantly suppressed in DPP-4-deficient diabetic rats. Our present study suggests that DPP-4 deficiency could exert beneficial actions on type 1 diabetic nephropathy partly by blocking the AGE-RAGE axis. DPP-4 might be a novel therapeutic target for preventing diabetic nephropathy. Sugars, including glucose and fructose, can react nonenzymatically with the amino groups of proteins, lipids and nucleic acids to form reversible Schiff bases, and then Amadori products. 1-3 These early glycation products undergo further complex reactions such as rearrangement, dehydration and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives called 'advanced glycation end products (AGEs)'. 1-3 The process of non-enzymatic glycation is also known as Maillard reaction, and formation and accumulation of AGEs in various tissues have progressed at a physiological aging and at an extremely accelerated rate under diabetes. [1][2][3] There is a growing body of evidence that AGEs and their receptor (RAGE) interaction evoke oxidative stress generation and inflammatory and fibrotic reactions, thereby causing progressive alteration in renal architecture and loss of renal function in diabetes. [4][5][6][7][8] Furthermore, RAGEoverexpressing diabetic mice have been shown to exhibit progressive glomerulosclerosis with renal dysfunction, compared with diabetic littermates lacking the RAGE transgene. 9 Diabetic homozygous RAGE null mice displayed diminished albuminuria and glomerulosclerosis and failed to develop significantly increased mesan...

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“…This is consistent with studies in humans with SCCs, rheumatoid arthritis and lupus erythematosus (Cordero et al, 2009). Changes in sCD26 levels are often associated with immune status changes: low concentrations of sCD26 are correlated with failure of the immune response (for example, in solid tumours), whereas high concentrations are found in inflammatory and infectious diseases (Cordero et al, 2009). Inhibition of CD26 with SG did not affect the onset of wound-induced tumour formation, but did result in reduced tumour size.…”

Section: Discussionmentioning

confidence: 99%

“…Biological fluids, such as serum, contain relatively high levels of soluble CD26 (sCD26), but the physiological role of sCD26 and its mode of release from the cell surface are incompletely characterised (Cordero et al, 2009) between WT (n ¼ 6) and tumour-free InvEE (n ¼ 5) mice, but activity was significantly lower in tumour-bearing InvEE animals (n ¼ 5, Po0.05; Figure 1g). The serum concentration of sCD26 was lower in both tumour-free and tumour-bearing InvEE mice compared with WT controls (Po0.05; Figure 1h).…”

Section: Elevated Cd26 Levels and Activity In Invee Epidermismentioning

confidence: 99%

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

et al. 2011

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We have previously described InvEE transgenic mice in which non-dividing, differentiating epidermal cells express oncogenically activated MAPK kinase 1 (MEK1). Skin wounding triggers tumour formation in InvEE mice via a mechanism that involves epidermal release of IL-1a and attraction of a pro-tumorigenic inflammatory infiltrate. To look for potential effects on the underlying connective tissue, we screened InvEE and wild-type epidermis for differential expression of cytokines and immune modulators. We identified a single protein, CD26 (dipeptidyl peptidase-4). CD26 serum levels were not increased in InvEE mice. In contrast, CD26 was upregulated in keratinocytes expressing mutant MEK1 and in the epithelial compartment of InvEE tumours, where it accumulated at cell-cell borders. CD26 expression was increased in dermal fibroblasts following skin wounding but was downregulated in tumour stroma. CD26 activity was stimulated by calcium-induced intercellular adhesion in keratinocytes, suggesting that the upregulation of CD26 in InvEE epidermis is due to expansion of the differentiated cell layers. IL-1a treatment of dermal fibroblasts stimulated CD26 activity, and therefore epidermal IL-1a release may contribute to the upregulation of CD26 expression in wounded dermis. Pharmacological blockade of CD26, via Sitagliptin, reduced growth of InvEE tumours, while combined inhibition of IL-1a and CD26 delayed tumour onset and reduced tumour incidence. Our results demonstrate that inappropriate activation of MEK1 in the epidermis leads to changes in dermal fibroblasts that, like the skin inflammatory infiltrate, contribute to tumour formation.

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On the origin of serum CD26 and its altered concentration in cancer patients

Cited by 186 publications

References 314 publications

Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)

Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

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