Dipeptidyl peptidase IV (DPP4) deficiency increases Th1-driven allergic contact dermatitis

Tasic, Tihana; Bäumer, Wolfgang; Schmiedl, Andreas; Schwichtenhövel, F.; Pabst, Reinhard; Raap, Ulrike; Hörsten, Stephan von; Stephan, Michael

doi:10.1111/j.1365-2222.2011.03778.x

Cited by 31 publications

(31 citation statements)

References 46 publications

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“…Treatment with DPP4 inhibitors reduced leukocyte counts and, in particular, T cell and B cell infiltration in 2 murine models of SSc, both of which are centrally involved in the pathogenesis of SSc (1,46). Indeed, DPP4 has been shown to regulate Th2 polarization and regulate B cell activation (47)(48)(49)(50). Despite the potent effects on B cell and T cell infiltration into fibrotic tissues, our bone marrow transplantation experiments actually demonstrated that the profibrotic effects of DPP-4 required that DPP-4 be predominantly expressed in tissue-resident cells such as fibroblasts.…”

Section: Discussionmentioning

confidence: 81%

Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis

Soare

Györfi

Matei

et al. 2019

Arthritis & Rheumatology

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Objective Expression of dipeptidylpeptidase 4 (DPP‐4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP‐4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP‐4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). Methods Expression of DPP‐4 in skin biopsy samples and dermal fibroblasts was analyzed by real‐time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP‐4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). Results The expression of DPP‐4 and the number of DPP‐4–positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)–dependent manner. DPP‐4–positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ‐induced ERK signaling. DPP4‐knockout mice were less sensitive to bleomycin‐induced dermal and pulmonary fibrosis (P < 0.0001 versus wild‐type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft‐versus‐host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. Conclusion DPP‐4 characterizes a population of activated fibroblasts and shows that DPP‐4 regulates TGFβ‐induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well‐tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.

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Section: Discussionmentioning

confidence: 81%

Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis

Soare

Györfi

Matei

et al. 2019

Arthritis & Rheumatology

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“…CD26/DPP4 appears to play a role in a number of other diseases (see Table ). In atopic dermatitis, CD26/DPP4 expression was up‐regulated in the skin biopsies of patients compared with healthy controls, as well as in both models of contact hypersensitivity . In psoriasis, reduced expression of CD26/DPP4 on CD8 + T cells has been observed .…”

Section: Involvement Of Cd26/dpp4 In Pathologymentioning

confidence: 99%

Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system

Klemann

Wagner

Stephan

et al. 2016

Clinical and Experimental Immunology

373

437

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SummaryCD26/DPP4 (dipeptidyl peptidase 4/DP4/DPPIV) is a surface T cell activation antigen and has been shown to have DPP4 enzymatic activity, cleaving-off amino-terminal dipeptides with either L-proline or L-alanine at the penultimate position. It plays a major role in glucose metabolism by Nterminal truncation and inactivation of the incretins glucagon-like peptide-1 (GLP) and gastric inhibitory protein (GIP). In 2006, DPP4 inhibitors have been introduced to clinics and have been demonstrated to efficiently enhance the endogenous insulin secretion via prolongation of the half-life of GLP-1 and GIP in patients. However, a large number of studies demonstrate clearly that CD26/DPP4 also plays an integral role in the immune system, particularly in T cell activation. Therefore, inhibition of DPP4 might represent a double-edged sword. Apart from the metabolic benefit, the associated immunological effects of long term DPP4 inhibition on regulatory processes such as T cell homeostasis, maturation and activation are not understood fully at this stage. The current data point to an important role for CD26/DPP4 in maintaining lymphocyte composition and function, T cell activation and co-stimulation, memory T cell generation and thymic emigration patterns during immune-senescence. In rodents, critical immune changes occur at baseline levels as well as after in-vitro and in-vivo challenge. In patients receiving DPP4 inhibitors, evidence of immunological side effects also became apparent. The scope of this review is to recapitulate the role of CD26/DPP4 in the immune system regarding its pharmacological inhibition and T cell-dependent immune regulation.Keywords: autoimmunity, B cell, cell activation, chemokines, T cells Structure and characterization of CD26Originally described 50 years ago [1], the lymphocyte cell surface protein CD26 possess a dipeptidyl peptidase-4 (DPP4) activity. It cleaves dipeptides from the N-termini of oligopeptides and smaller peptides with proline or alanine at the penultimate position, as illustrated in Fig. 1b [International Union of Biochemistry and Molecular Biology (IUBMB) Enzyme Nomenclature EC 3.4.14.5].CD26/DPP4 is a homodimer and an integral type II glycoprotein anchored to the membrane by its signal peptide. The primary structure consists of a short six amino acid cytoplasmic tail, a 22 amino acid transmembrane, a 738 amino acid extracellular portion comprised of a flexible stalk, glycosylation-rich region, cysteine-rich region and catalytic region with the catalytic triad Ser 630 , Asp 708 and His 740 (Fig. 1e). Recent studies have revealed that the transmembrane region contributes to enzyme activity and quaternary structure by dimerization [2]. The crystal structure of human CD26/DPP4 has been elucidated to reveal two domains: an eight-bladed propeller and an a/b-hydrolase domain. The propeller is open and consists of two subdomains made up of blades II-V and VI-VIII for the glycosylation-rich and cysteine-rich regions, respectively (Fig. 1d). Most monoclonal anti-CD26/DPP4 antibodies,...

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“…CD26 enzymatic activity downmodulates the biological function of most of these chemokines and cytokines (Table 3). Consistent with this observation, it has been found that CD26 inhibitors can enhance some in vivo immune responses depending on the dose, application route, timing or predominant Teff subset [45,169], which could be explained by the presence of offtarget effects as well [25,170]. However, animal models of rheumatoid arthritis [93], multiple sclerosis [171] and inflammatory bowel disease [172] in CD26 KO mice do support an immunosuppressive role of both CD26 and DPP4 activity.…”

Section: Inhibitory Functions Of Both Membrane and Soluble Cd26 On Asmentioning

confidence: 58%

CD26 and Asthma: a Comprehensive Review

Nieto‐Fontarigo

González‐Barcala

José³

et al. 2016

Clinic Rev Allerg Immunol

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Asthma is a heterogeneous and chronic inflammatory family of disorders of the airways with increasing prevalence that results in recurrent and reversible bronchial obstruction and expiratory airflow limitation. These diseases arise from the interaction between environmental and genetic factors, which collaborate to cause increased susceptibility and severity. Many asthma susceptibility genes are linked to the immune system or encode enzymes like metalloproteases (e.g., ADAM-33) or serine proteases. The S9 family of serine proteases (prolyl oligopeptidases) is capable to process peptide bonds adjacent to proline, a kind of cleavage-resistant peptide bonds present in many growth factors, chemokines or cytokines that are important for asthma. Curiously, two serine proteases within the S9 family encoded by genes located on chromosome 2 appear to have a role in asthma: CD26/dipeptidyl peptidase 4 (DPP4) and DPP10. The aim of this review is to summarize the current knowledge about CD26 and to provide a structured overview of the numerous functions and implications that this versatile enzyme could have in this disease, especially after the detection of some secondary effects (e.g., viral nasopharyngitis) in type II diabetes mellitus patients (a subset with a certain risk of developing obesity-related asthma) upon CD26 inhibitory therapy.

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Dipeptidyl peptidase IV (DPP4) deficiency increases Th1-driven allergic contact dermatitis

Cited by 31 publications

References 46 publications

Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis

Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis

Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system

CD26 and Asthma: a Comprehensive Review

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