A High Endothelial Venule Secretory Protein, Mac25/Angiomodulin, Interacts with Multiple High Endothelial Venule-Associated Molecules Including Chemokines

Abstract

We previously reported that mac25/angiomodulin (AGM), a 30-kDa secretory protein, is abundantly expressed in high endothelial venules (HEVs), which play a crucial role in lymphocyte trafficking to the lymph nodes and Peyer’s patches. We report that mac25/AGM interacts preferentially with certain molecules that are expressed in or around HEVs. In particular, mac25/AGM interacted with not only the extracellular matrix proteins and glycosaminoglycans that are expressed in most blood vessels including HEVs, but also with some chemokines that are implicated in the regulation of lymphocyte trafficking, such as the secondary lymphoid-tissue chemokine (SLC; CCL21), IFN-γ-inducible protein 10 (IP-10; CXCL10), and RANTES (CCL5). The binding of mac25/AGM to SLC and IP-10 was dose-dependent and saturable. The binding to IP-10 could be inhibited by SLC but not by a non-mac25/AGM-binding chemokine, EBI1-ligand chemokine (ELC; CCL19). Interestingly, mac25/AGM failed to interact with 18 other chemokines, suggesting that it binds to certain chemokines preferentially. Immunohistochemical analysis indicated that mac25/AGM colocalizes at least partially with SLC and IP-10 at the basal lamina of HEVs. Upon binding with mac25/AGM, SLC and IP-10 retained all their Ca2+-signaling activity in vitro, suggesting that mac25/AGM can hold and present chemokines in the basal lamina of HEVs. These results imply that mac25/AGM plays a multifunctional role, serving not only as an adhesion protein to interact with glycosaminoglycans and extracellular matrix proteins but also as a molecule to present chemokines so that lymphocytes extravasating through HEVs receive further directional cues subsequent to the luminal encounter with lymphoid chemokines.

IGFBP7 participates in the reciprocal interaction between acute lymphoblastic leukemia and BM stromal cells and in leukemia resistance to asparaginase

“…As shown in Figure 6a, rIGFBP7 induced a clear increase in ASNS expression in a time-dependent manner, being maximal (twofold) after 6 h. IGFBP7 is known to act through the binding to different IGFs and chemokines. 34,35 Some of these soluble factors are known to be secreted by BMSCs, 44 --46 thus mediating the observed effects of rIGFBP7 addition with no ligand, in serum-free medium.…”

CXC Chemokine Ligand 12 Promotes CCR7-Dependent Naive T Cell Trafficking to Lymph Nodes and Peyer’s Patches

“…CXCL13 selectively acts on B cells through its receptor, CXCR5, and is involved in B cell trafficking to Peyer's patches (PPs) (9) and lymph nodes (LNs) (10). Previous studies, including ours, indicate that these chemokines are not only produced in situ but also are sequestered locally via a variety of locally expressed chemokine-binding molecules such as mac25/ angiomodulin (11), collagen type IV (12), fibronectin (12,13), laminin (12), heparan sulfate (14), and possibly oversulfated chondroitin sulfates (15). As a result, oligomerized chemokines are implicated in promoting directional lymphocyte trafficking from HEVs into the lymphoid tissue parenchyma by being presented to circulating lymphocytes at high concentrations in a geographically regulated manner (2).…”

Insulin-Like-Growth Factor-Binding-Protein 7: An Antagonist to Breast Cancer

“…The protein was localized at the apical part of the luminal and glandular epithelium, as well as in stromal and endothelial cells [53]. Strong expression of IGFBP7 has also been seen in high endothelial vessels (HEV) [50].…”

“…IGFBP7 also can bind to cell surface-associated heparin sulfate proteoglycans, specifically, syndecan-1 [40]. IGFBP7 has also been shown to bind certain CC chemokines, specifically, RANTES, SLC, and the CXC chemokine, IP-10 [50].…”