Intestinal APCs of the endogenous nanomineral pathway fail to express PD-L1 in Crohn's disease.

Crohn's disease is a chronic inflammatory condition most commonly affecting the ileum and colon. The aetiology of Crohn's disease is complex and may include defects in peptidoglycan recognition, and/or failures in the establishment of intestinal tolerance. We have recently described a novel constitutive endogenous delivery system for the translocation of nanomineral-antigen-peptidoglycan (NAP) conjugates to antigen presenting cells (APCs) in intestinal lymphoid patches. In mice NAP conjugate delivery to APCs results in high surface expression of the immuno-modulatory molecule programmed death receptor ligand 1 (PD-L1). Here we report that NAP conjugate positive APCs in human ileal tissues from individuals with ulcerative colitis and intestinal carcinomas, also have high expression of PD-L1. However, NAP-conjugate positive APCs in intestinal tissue from patients with Crohn's disease show selective failure in PD-L1 expression. Therefore, in Crohn's disease intestinal antigen taken up by lymphoid patch APCs will be presented without PD-L1 induced tolerogenic signalling, perhaps initiating disease.

Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes.

The Nrf2/antioxidant response element (ARE) signaling pathway plays a key role in activating cellular antioxidants, including heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO1), and glutathione. Protein kinase C (PKC) may also regulate these antioxidants, as PKC phosphorylates Nrf2 in vitro. This study examined the role of PKC in ARE-mediated gene regulation in human monocytes by curcumin, a potent inducer of the Nrf2/ARE pathway. Curcumin increased HO-1 and glutamyl cysteine ligase modulator (GCLM) expression and stimulated Nrf2 binding to the ARE. Curcumin also rapidly stimulated PKC phosphorylation and Ro-31-8220, a pan-PKC inhibitor, decreased curcumin-induced GCLM and HO-1 mRNA expression and ARE binding. Rottlerin (a PKC delta inhibitor) and PKC delta antisense oligonucleotides significantly inhibited curcumin-induced GCLM and HO-1 mRNA expression and ARE binding. Furthermore, a p38 MAP kinase inhibitor reduced GCLM and HO-1 expression and rottlerin inhibited curcumin-induced p38 phosphorylation. In summary, curcumin activates ARE-mediated gene expression in human monocytes via PKC delta, upstream of p38 and Nrf2.

Developmental changes in leptin as a measure of energy status in human infants in a natural ecologic setting.

BACKGROUND: Most human research on leptin has involved well-nourished subjects or clinical states such as anorexia nervosa or cancer cachexia. OBJECTIVE: We studied the development of leptin as a monitor of energy status in young African infants whose growth patterns probably reflect the evolutionary norm. DESIGN: We enrolled a prospective birth cohort of 138 rural Gambian mother-infant pairs. Plasma leptin was analyzed in maternal blood in late pregnancy, in cord blood, and at 8, 16, and 52 wk in the infants. Body mass index (BMI; in kg/m2) was used as a proxy for fatness. The mothers were lean (BMI: 21.6+/-2.5), and the infants grew poorly compared with Western standards (average weight-for-age z score of -1.9 at 52 wk). RESULTS: Maternal and cord blood leptin and birth weight were all positively correlated. Throughout infancy, leptin was highly correlated with BMI. A strong sex difference existed at birth (ie, leptin concentrations were significantly higher in females than in males), disappeared at 8 wk, and reappeared at 16 and 52 wk. Absolute leptin concentrations declined by almost 90% from birth to 52 wk, but leptin's ability to discriminate across a range of BMI values improved with age. In early infancy, leptin concentrations were uncorrelated with recent changes in BMI, but, by 52 wk, leptin was able to assess both the size of energy stores and the direction of recent changes. CONCLUSIONS: Leptin concentrations signal energy status from fetal life onward. As infancy progresses, leptin's power to discriminate both chronic and dynamic energy status increases, and this discrimination is achieved at much lower circulating peptide concentrations.