CD166/ALCAM Mediates Proinflammatory Effects of S100B in Delayed Type Hypersensitivity

Abstract

Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation. Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE−/− mice by 50% (p < 0.001). This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE. This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-κB family in wild type (WT) and RAGE−/− mouse endothelial cells. Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-κB activation in RAGE−/−, but not in WT cells. The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE−/− animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p < 0.001). Experiments in ALCAM−/− animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa. Consistently, ALCAM−/− mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM−/− RAGE−/− double-knockout mice show a 27% reduction in DTH reaction. Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart.

Activated leucocyte cell adhesion molecule (ALCAM/CD166) regulates T cell responses in a murine model of food allergy

“…Furthermore, WT mice that received OVA-pulsed ALCAM -/-BMDCs yielded weaker immune responses and slower total cell proliferation. These findings indicate that ALCAM promotes immune responses in food allergy, and these data correlate well with other studies that demonstrated the role of ALCAM in malignant mesothelioma and delayed-type hypersensitivity [16,32]. In malignant mesothelioma, knock-down of ALCAM led to 30-50% inhibition of cell migration and invasion of mesothelioma cells [32].…”

Increased Expression of EGR-1 in Diabetic Human Adipose Tissue-Derived Mesenchymal Stem Cells Reduces Their Wound Healing Capacity

“…CD166/AL-CAM expressed higher in dAT-MSCs compared with nATMSCs. It has been reported that CD166/ALCAM is a close structural and functional homolog of RAGE [33], and RAGE-mediated regulation of adiposity and inflammation associated with T2DM and diabetic vascular complications [34]. Collectively, these findings demonstrate that of these two types of AT-MSCs, dAT-MSCs possess a greater potential to differentiate into adipocytes; the other phenotypes were indistinguishable from nAT-MSCs.…”

The advanced glycation end‐product Nϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

“…The mRNA levels of the genes coding for (1) RAGE, (2) CD166/activated leukocyte cell adhesion molecule (ALCAM), a close structural and functional homologue of RAGE , (3) nuclear factor of activated T‐cells cytoplasmic 1 (NFATC1) and serine/threonine protein kinase Pim‐1 (PIM1), two signal transducer and activator of transcription 3 (STAT3) downstream targets that have been implicated in inflammation‐driven PaC and (4) interleukin (IL)‐6, the production of which has been shown to be RAGE‐dependent in Pdx1‐Cre;LSL‐Kras G12D/+ (KC) mice ( AGER , ALCAM , NFATC1 , PIM1 , and IL6 , respectively) were assessed by real‐time polymerase chain reaction (RT‐PCR) with a StepOne Real‐Time PCR System and TaqMan Gene Expression assays (Applied Biosystems, Monza, Italy), and are listed in supplementary material, Table S1 .…”