Ksp-Cadherin CDH16(CDH16/1071), APC conjugate

Ksp-Cadherin, APC conjugate
Ksp-Cadherin, APC conjugate

Ksp-Cadherin / CDH16 (CDH16 / 1071), APC conjugate, 0.1mg / mL

Manufacturer Biotium
  • Antibody
Type Antibody Primary
Specific against other
crowd 250 ul
Item No B-BNCA1071-250
eClass 6.1 32160702
eClass 9.0 32160702
Temperature storage condition
2C to 8C

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Recombinant full-length human Cadherin-16 protein
Cell Surface with some cytoplasmic
This MAb recognizes a protein of 130kDa, identified as Ksp-cadherin. Cadherins form a superfamily of related glycoproteins that mediate calcium-dependent cell adhesion and transmit signals from the extracellular matrix to the cytoplasm. Cadherins have been implicated in embryogenesis, tissue morphogenesis, tissue structure maintenance, cell polarization, neoplastic invasiveness and metastasis, and membrane transport. It is suggested that Ksp-cadherin is a marker for terminal differentiation of the basolateral membranes of renal tubular epithelial cells. Within the kidney, Ksp-Cadherin is found exclusively in the basolateral membrane of renal tubular epithelial cells and collecting duct cells, and not in glomeruli, renal interstitial cells, or blood vessels.Ksp-Cadherin has been suggested to distinguish Chromophobe Renal-Cell Carcinoma from Oncocytoma.
IgG1 Kappa
Protein A or G purified
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Interleukin-23 reshapes kidney resident cell metabolism and promotes local
kidney inflammation
Hao Li1
, Maria Tsokos1
, Rhea Bhargava1
, Iannis Adamopoulos1
, Hanni Menn-Josephy2
, Isaac E.
, Philip Rosenstiel4
, Jarrat Jordan5
, George C. Tsokos1
1Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 2Department of Medicine, Renal Section, Boston University School of Medicine, Boston MA 3Departments of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 4 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, Germany 5 Janssen Research & Development, LLC, Spring House, PA, USA
Interstitial kidney inflammation is present in various nephritides in which serum IL-23 is elevated.
Here we showed that IL-23 receptor (IL-23R) expressing murine and human renal tubular
epithelial cells (TEC) responded to IL-23 by inducing intracellular calcium flux, enhanced
glycolysis, and the upregulation of calcium/calmodulin kinase IV (CaMK4) which resulted in
suppression of the expression of the arginine degrading enzyme arginase 1 (ARG1) thus increasing in situ levels of free L-Arginine. Limited availability of arginine suppressed the ability of infiltrating T cells to proliferate and produce inflammatory cytokines. TEC from humans and mice with nephritis express increased levels of IL-23R and CaMK4 but reduced levels of ARG1.

TECspecific deletion of Il23r or Camk4 suppressed inflammation whereas deletion of Arg1 exacerbated inflammation in different murine disease models. Finally, TEC-specific delivery of a CaMK4 inhibitor specifically curbed renal inflammation in lupus-prone mice without affecting systemic inflammation. Our data offer first evidence on the immunosuppressive capacity of TEC through a mechanism that involves competitive uptake of arginine and signify the importance of modulation of an inflammatory cytokine on the function of non-lymphoid cells, which leads to the establishment of an inflammatory microenvironment. New approaches to treat kidney inflammation should consider restoring the immunosuppressive capacity of TEC.

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Interstitial inflammation is frequently present in patients with autoimmune kidney diseases (1).The presence of renal infiltrating immune cells including monocytes (2-4), B cells (5, 6) and T cells (7) has been linked to fibrosis and kidney failure (8), and thus is a well-recognized risk factor for morbidity and mortality (9). Intrarenal T cells recognize kidney specific antigens and proliferate locally (10-12). Local microenvironment factors including hypoxia (13) and nutrient concentration (14, 15), which may be altered in inflammatory conditions, regulate the survival and pathogenesis of infiltrating T cells (16, 17). Cellular metabolism has emerged as an important determinant of T cell fate and function (18, 19). The competitive uptake of nutrients by tissue resident cells may reshape the local immune response by altering the availability of nutrients (20), which implies that in kidneys, resident cells like tubular epithelial cells (TEC), mesangial cells, endothelial cells or podocytes may function not only as victims but also active contributors to the
development of renal inflammation (21).

Interleukin-23 (IL-23) is a heterodimeric cytokine of the IL-12 superfamily (22) which exhibits a  proinflammatory role through its ability to contribute to the generation of Th17 cells (23). Yet, it is unknown whether IL-23 may alter the function of non-lymphoid cells. The IL-23/IL-17 pathway has been reported to contribute to the pathogenesis of kidney disease characterized by chronic renal inflammation (24-27). Here we show that in the absence of additional inflammatory signals, IL-23 alone drives kidney inflammation characterized by massive T lymphocyte infiltration.
Furthermore, genetic ablation of the IL-23 receptor (IL-23R) in renal tubular epithelial cells
limited kidney inflammation in different models of murine renal disease. Mechanistically, we show that IL-23 acts directly on TEC to initiate intracellular calcium flux and enhance the expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) (28), which
results in the suppression of the expression of arginine-hydrolyzing enzyme arginase 1 (ARG1) (29). Arginine is a semi-essential amino acid that plays a central role in the regulation of the immune response and in its absence T cell proliferation is abolished (30, 31). Therefore, IL-23 mediated downregulation of ARG1 in TEC establishes an inflammatory milieu by providing arginine which promotes local T cell activation and proliferation. Collectively, our results reveal
that kidney TEC exert a local an immunosuppressive role which is negated in the presence of IL23.


IL-23 is sufficient to instigate kidney inflammation. The elevation of serum IL-23 in patients with active SLE plus the fact that this elevation preceded the appearance of proteinuria (Supplemental Figure 1) affirmed the hypothesis that IL-23/IL-17 axis contributed to the pathogenesis of various types of nephritis (7, 23, 32), however, it remains unknown whether these cytokines could act on resident kidney cells directly. To investigate the
role of IL-23 in renal inflammation, we overexpressed IL-23 in wild type 8-week-old C57BL/6J mice by hydrodynamic administration of a minicircle (MC) cDNA construct encoding IL-23p19 and IL-12/23p40 (IL-23 MC) while GFP MC was used as control (Supplemental Figure 2) (33, 34). Hydrodynamic delivered IL-23 MC has been shown to induce psoriatic arthritis like symptoms in male B10.RⅢ mice (33-35). As expected, skin inflammation and injury developed in these C57BL/6J receiving single dose IL-23 MC (Supplemental Figure 3), however, arthritis was not observed.

The discrepancy could be explained by different major histocompatibility complex (MHC) haplotypes. Interestingly, we further observed that in vivo expression of IL-23
in C57BL/6J was sufficient to phenocopy the tubulointerstitial inflammation component
(Supplementary Figure 4, Figure 1A) frequently documented in human nephritis which predicts renal failure (8). Mice which received GFP MC did not develop tubulointerstitial inflammation (Supplemental Figure 4). Confocal image analysis revealed gradual accumulation of renal immune cell infiltration including T cells, activated monocytes and neutrophils 30 days after IL23 MC administration (Figure 1B). Analysis of renal immune cell infiltrates by flow cytometry confirmed the emergence of CD4 T cells (Figure 1C, Supplemental Figure 4, 5), at a time later than the accumulation of activated CD4 T cells especially Th17s in the spleen as part of systemic inflammation (Supplemental Figure 6). T helper cells are important for activating and recruiting neutrophils and macrophages to the site of inflammation. As expected, accumulation of Gr-1 +
activated macrophages and neutrophils in the tubulointerstitial space was also observed (Figure 1C, Supplemental Figure 4, 5). Of note, proteinuria was observed in mice which received IL-23 MC but not GFP MC (Figure 1D). Increased ratio of the urinary 2-microglobulin and 4 albumin to creatinine indicated the renal tubular malfunction and podocyte failure (Figure 1D) (36).

Epithelial IL-23 signaling initiates calcium flux and promotes glycolysis. Having demonstrated that IL-23 alone can initiate and propagate renal inflammation, we asked
whether there were kidney resident cells responding to IL-23 prior to the development of renal inflammation. To address this question, GFP or IL-23 MC were administered to naive B6 mice for 24 hours only. When elevated circulating IL-23 but not renal immune cell infiltration was observed, kidneys were harvested to examine IL-23R protein expression on resident cells. Interestingly, elevated IL-23R expression was observed in kidneys from mice administered IL-23 MC but not those administered control GFP MC (Figure 2A). The antibody binding specificity was validated using polarized T cells (Supplemental Figure 7). Confocal images further confirmed the increase of IL-23R mainly on CD26+
tubular epithelial cells (37, 38) (Figure 2B). In order to comprehensively characterize IL-23-initiated signaling events in kidney resident cells, primary TEC were sorted from B6 mice injected with either GFP or IL-23 MC (Supplemental Figure 8) and the mRNA expression levels of different genes were assessed using a customized PCR array
which revealed that TEC displayed a completely different gene expression pattern upon IL-23 stimulation in vivo. Notably, a number of IL-23 associated genes such as Stat3, Il23r, Jak2 and Socs3 were significantly enriched along with increased expression of Camk4 but not Camk2 (Figure 2C). To further validate the direct impact of IL-23 on TEC, proximal TEC were isolated from naïve B6 mice and selectively enriched in vitro (39). The expression of IL-23-related genes was increased in TEC following stimulation with IL-23 in a time-dependent fashion (Figure 2D).
Calcium-dependent mechanisms play pivotal roles in kidney function (40) and TEC are among the cells which are sensitive to cellular calcium changes (41). Interestingly, a modest but significant increase of calcium flux was observed in mouse primary renal proximal TEC stimulated with IL-23 (Figure 2E). Since calcium is integral in many important aspects of cell biology including cell metabolism, we quantified glycolysis and mitochondrial respiration through the measurement of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively (42, 43). Increased ECAR but not OCR was observed in IL-23-stimulated primary

TEC (Figure 2F, Supplemental Figure 9). Interestingly, this enhancement was abrogated
following the addition of EGTA, a chelating agent with a high affinity for calcium ions, which
5 indicated IL-23 boosted glycolysis was calcium-dependent. Considering that Ca2+/CalmodulinDependent Protein Kinase Kinases (CaMKKs) are serine/threonine kinases activated by the binding of Ca2+/CaM which helps remove the auto-inhibitory domain and enables substrate access (44), the IL-23 induced intracellular calcium flux might lead to enhanced CaMK4 expression and activation.

To validate this supposition, mouse TEC cultured in the presence or absence of IL-23 were collected and subjected to Western blot analysis. Indeed, increased IL-23R and CaMK4 but not CaMK2 were observed in TEC stimulated with IL-23 (Figure 2G), which was further
confirmed by confocal image analysis (Figure 2H). Furthermore, to extend our observations in vitro, the expression of CaMK2 and CaMK4 were assessed in the kidneys of mice administered GFP or IL-23 MC. As expected, immunohistochemistry staining revealed a significant increase of CaMK4 but not of CaMK2 in TEC from IL-23 MC administered mice (Figure 2I). Collectively, our data indicated that, TEC responded to IL-23 by upregulating CaMK4, which might control cellular processes related to immune functions.


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