Circulating CD26 is negatively associated with inflammation in human and experimental arthritis

Dipeptidyl peptidase IV (DPPIV, CD26), a protease-cleaving N-terminal X-Pro dipeptide from selected proteins including some chemokines, is expressed both as a soluble form in plasma and on the cell surface of various immune and nonimmune cell types. To gain insights into the pathophysiological role of CD26 in arthritis, we explored DPPIV/CD26 expression during murine antigen-induced arthritis (AIA), an experimental model of arthritis. AIA induction led to reduced plasma DPPIV activity. In CD26-deficient mice, the severity of AIA was increased as assessed by enhanced technetium uptake and by increased histological parameters of inflammation (synovial thickness and exudate). We demonstrated that CD26 controls the in vivo half-life of the intact active form of the proinflammatory chemokine stromal cell-derived factor-1 (SDF-1). CD26-deficient mice exhibited increased levels of circulating active SDF-1, associated with increased numbers of SDF-1 receptor (CXCR4)-positive cells infiltrating arthritic joints. In a clinical study, plasma levels of DPPIV/CD26 from rheumatoid arthritis patients were significantly decreased when compared to those from osteoarthritis patients and inversely correlate with C-reactive protein levels. In conclusion, decreased circulating CD26 levels in arthritis may influence CD26-mediated regulation of the chemotactic SDF-1/CXCR4 axis.     

Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome.

PURPOSE: EBV-latent membrane protein-1 (LMP-1) is often expressed in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin's lymphoma (cHL), but its clinical significance is controversial. We correlated LMP-1 with presenting features, including serum interleukin 10 levels and clinical outcome. EXPERIMENTAL DESIGN: Patients were eligible if they had biopsy-proven cHL, were untreated, HIV-1 negative, and had available archival tissue. LMP-1 expression was determined by immunohistochemistry. RESULTS: We identified 577 patients with cHL with a median age of 30 years, 55% of whom were male. LMP-1 was expressed in HRS cells of 124 patients (21%) and was detected in 78 of 461 (17%) patients with nodular sclerosis compared with 44 of 112 (39%) with mixed cellularity (P < 0.001 by Fisher's exact test). Patients with tumors with LMP-1-positive HRS cells had higher serum interleukin 10 levels (P = 0.009 by Mann-Whitney test). For the 303 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens, the 5-year failure-free survival (FFS) for those with LMP-1-positive tumors was 74% compared with 81% for those with LMP-1-negative tumors (P = 0.23, by log-rank test). Overall survival (OS) at 5 years for patients with LMP-1-positive tumors was 90 versus 91% for patients with LMP-1-negative tumors (P = 0.8 by log-rank test). Expression of LMP-1 was not associated with different FFS and OS in patients treated with other regimens or with radiotherapy alone. CONCLUSIONS: LMP-1 was expressed by HRS cells in 21% of cHL and correlated with mixed cellularity type and higher serum interleukin 10 levels. The presence of LMP-1 was not associated with FFS or OS in uniformly treated patients.     

Sustained Bundle Branch Reentry in a Patient with Hypertrophic Cardiomyopathy and Nondilated Left Ventricle

Ventricular tachycardia is a well-known complication in patients withhypertrophic cardiomyopathy. We report the case of a patient withhypertrophic cardiomyo<->pathy with easily inducible monomorphic ventriculartachycardia. Electrophysiology study demonstrated that bundle branch reentrywas the mechanism of the tachycardia. The tachycardia was renderednon-inducible by radiofrequency ablation of the right bundle branch.     

TCL1 expression in plasmacytoid dendritic cells (DC2s) and the related CD4+ CD56+ blastic tumors of skin

Initially considered to be of natural killer (NK)-cell origin, CD4+ CD56+ blastic tumors (BTs) of skin have recently been proposed to be of dendritic cell lineage. We have previously described BTs with transformation to myelomonocytic leukemia. Here we report expression of the lymphoid proto-oncogene TCL1 in 10 (83%) of 12 BTs and in lymph node plasmacytoid dendritic cells (DC2s). TCL1 was also expressed in myelomonocytic blasts of 3 transformed BT cases but not in true NK-cell tumors (n = 18), de novo acute myelomonocytic leukemias (1 of 14, 7%), or mature T-cell malignancies (1 of 112, < 1%), with the exception of T-prolymphocytic leukemia (T-PLL). All BT cases were also positive for the DC2-associated marker CD123. These results further support derivation of BTs from DC2s, and demonstrate that TCL1 expression in this tumor is common to the immature blastoid, lymphoid-appearing, and subsequent myelomonocytic phases of this disease.     

TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state.

Expression of the human oncogene TCL1 in transgenic mice produces B-cell tumors that resemble chronic lymphocytic leukemia (CLL) suggesting its role in B-cell tumorigenesis. To clarify the expression pattern and regulation of TCL1 in CLL, we assessed 213 primary tumors by immunohistochemistry (IHC), flow-cytometry and/or Western blot, using a new monoclonal antibody. TCL1 protein was detectable in the majority of CLL (90% by IHC) but showed marked variations across cases with virtual absence in approximately 10% of tumors. Higher TCL1 levels correlated with markers of the 'pre-germinal center' CLL subtype including unmutated VH status (P=0.005), ZAP70 expression (P=0.007), and presence of chromosome 11q22-23 deletions (P=0.04). Intratumoral heterogeneity in TCL1 levels was also prominent and explained in part by markedly lower TCL1 expression in proliferating tumor cells. In vitro exposure of CLL cells to interleukin-4 (but not other growth factors) produced progressive and irreversible decrease in TCL1 protein levels in association with the onset of proliferation. TCL1 expression patterns in CLL are complex and highly dynamic and appear to reflect both the histogenetic subtypes of the disease and the growth parameters of individual tumors. The observed regulation pattern suggests that TCL1 may exert its effects predominantly in the unmutated/ZAP70-positive tumor subset.     

Muscle-type specific intramyocellular and hepatic lipid metabolism during starvation in wistar rats

The physiological dynamics of intramyocellular lipids (IMCLs) in different muscle types and of hepatocellular lipids (HepCLs) are still uncertain. The dynamics of IMCLs in the soleus, tibialis anterior, and extensor digitorum longus (EDL) muscles and HepCL during fed, 12- to 72-h starved, and refed conditions were measured in vivo by (1)H-magnetic resonance spectroscopy (MRS) in Wistar rats. Despite significant elevations of free fatty acids (FFAs) during starvation, HepCLs and IMCLs in soleus remained constant. In tibialis anterior and EDL, however, IMCLs increased significantly by 170 and 450% after 72 h of starvation, respectively. After refeeding, elevated IMCLs dropped immediately in both muscles. Total muscle long-chain acyl-CoAs (LCACoAs) remained constant during the study period. Hepatic palmitoleoyl-CoA (C16:1) decreased significantly during starvation while total hepatic LCACoAs increased significantly. Consistent with constant values for FFAs, HepCLs, IMCLs, and muscle LCACoAs from 12-72 h of starvation, insulin sensitivity did not change. We conclude that during starvation-induced adipocytic lipolysis, oxidative muscles dispose elevated FFAs by oxidation, while nonoxidative ones neutralize FFAs by reesterification. Both mechanisms might prevent impairment of insulin signaling by maintaining low levels of LCACoAs. Hepatic palmitoleoyl-CoA might have a special role in lipid metabolism due to its unique dynamic profile during starvation.     

Hepatobiliary elimination of bile acid-modified oligodeoxynucleotides in Wistar and TR- rats: evidence for mrp2 as carrier for oligodeoxynucleotides

As therapeutic antisense tools, oligonucleotides (ODNs) must enter cells to bind to their target structures. ODNs distribute in nearly each tissue with relatively high concentrations in kidney and liver from where excretion into urine and bile occurs. To investigate mechanisms involved in hepatic ODN transport, normal mixed backbone phosphodiester/phosphorothioate ODNs (n-ODN) and two different bile acid-conjugated mixed backbone ODNs (1BA-ODN and 2BA-ODN) were applied to two different rat strains, normal Wistar rats and Wistar TR- rats. In normal Wistar rats, concentration-dependent hepatobiliary elimination of the ODNs was observed with a remarkable increase of excretion of the cholic acid BA-ODN conjugates. In contrast to normal Wistar rats, n-ODN excretion into bile by TR- rats, a mutant Wistar rat strain lacking a functional multidrug resistance-associated protein 2 (mrp2) at the canalicular membrane, was strongly diminished, whereas these rats excreted an ODN conjugated with two cholic acid molecules (2BA-ODN) into bile. Concomitant application of substrates transported by mrp2 such as bromosulfophthalein (BSP) or the synthetic chlorogenic acid derivative S 3025 significantly reduced the biliary appearance of normal ODN and 2BA-ODN in Wistar rats and also in TR- rats. To inhibit the expression of cRNA derived from the Na+ -dependent taurocholate cotransporting polypeptide (Ntcp), antisense ODNs were constructed which fully retained the antisense properties when coupled with two bile acid molecules. The results indicate that ODNs are secreted via the mrp2 into bile. In the absence of mrp2, further excretory transport systems with affinity for bile acids seem to be relevant for their excretion. The results further indicate that bile acid tagged ODNs are useful tools for liver specific antisense therapy.     

The cardiac K+ channel KCNQ1 is essential for gastric acid secretion

BACKGROUND & AIMS: Gastric H+ secretion via the H+/K+-adenosine triphosphatase is coupled to the uptake of K+. However, the molecular identity of luminal K+ channels enabling K+ recycling in parietal cells is unknown. This study was aimed to investigate these luminal K+ channels. METHODS: Acid secretion was measured in vivo and in vitro; KCNQ1 protein localization was assessed by immunofluorescence, and acid-sensitivity of KCNQ1 by patch-clamp. RESULTS: We identified KCNQ1, which is mutated in cardiac long QT syndrome, as a K+ channel located in tubulovesicles and apical membrane of parietal cells, where it colocalized with H+/K+-adenosine triphosphatase. Blockade of KCNQ1 current by 293B led to complete inhibition of acid secretion. The putative KCNQ1 subunits, KCNE2 and KCNE3, were abundant in human stomach; KCNE1, however, was absent. Coexpression of KCNE3/KCNQ1 in COS cells led to an acid-insensitive current; KCNE2/KCNQ1 was activated by low extracellular pH. CONCLUSIONS: We identified KCNQ1 as the missing luminal K+ channel in parietal cells and characterized its crucial role in acid secretion. Because KCNE3 and KCNE2 are expressed in human stomach, one or both are candidates to coassemble with KCNQ1 in parietal cells. Thus, stomach- and subunit-specific inhibitors of KCNQ1 might offer new therapeutical perspectives for peptic ulcer disease.