Oncostatin M Enhances CCL21 Expression by Microvascular Endothelial Cells and Increases the Efficiency of Dendritic Cell Trafficking to Lymph Nodes

Abstract

CCL21, a lymphatic endothelial cell (LEC)-derived chemokine, and its receptor CCR7 regulate dendritic cell (DC) trafficking to lymph nodes (LN), but it is unclear how CCL21 expression is regulated. Oncostatin M (OSM) is an IL-6-like cytokine synthesized by activated DC and other leukocytes. In vitro, OSM (but not TNF-α) stimulated CCL21 mRNA and protein expression by human dermal microvascular EC (DMEC) in an ERK1/2-dependent fashion. Conditioned medium from OSM-treated DMEC stimulated CCL21-dependent chemotaxis of mouse bone marrow-derived DC (BMDC). Cultured BMDC expressed OSM, which was increased with the addition of LPS. Topical application of the contact-sensitizing hapten, trinitrochlorobenzene, resulted in enhanced OSM expression in the skin, whereas cutaneous injection of TNF-α did not. Injection of OSM into the footpad increased CCL21 mRNA expression in the draining LN by ∼10-fold and in mouse skin by ∼4-fold without increasing CCR7 mRNA. In vitro, OSM increased the permeability of DMEC and lung microvascular EC monolayers to FITC-dextran beads, and, in vivo, it enhanced accumulation of Evans blue dye in draining LN by ∼3-fold (p = 0.0291). Of note, OSM increased trafficking of BMDC injected in footpads to draining LN by 2-fold (p = 0.016). In summary, OSM up-regulates CCL21 expression in skin and draining regional LN. We propose that OSM is a regulator of CCL21 expression and endothelial permeability in skin, contributing to efficient migration of DC to regional LN.

Human Lymphatic Endothelial Cells Express Multiple Functional TLRs

“…We did not observe increased expression of CCL21 mRNA above baseline levels in primary LECs in response to any TLR ligand, and CCL21 was not expressed to detectable levels by the htert-HDLECs. In addition, the only cytokine in our studies that led to induction of CCL21 by LECs was OSM, which is consistent with previous findings in mixed endothelial cell populations (24). The lack of CCL21 expression by htert-HDLECs and the lack of its induction in the primary dermal and lung LECs suggest there might possibly be environmental cues from neighboring cells in these tissues that provide signals for basal and increased CCL21 expression, as has been suggested previously (34).…”

“…The expression of CCL21 by LECs is involved in this DC migration, because mature DCs express high levels of CCR7 (4). Treatment of skin with inflammatory cytokines can lead to increased production of CCL21, which in turn enhances migration of mature DCs to draining LNs (16), although the exact mechanism of this induction is not clear (24). We did not observe increased expression of CCL21 mRNA above baseline levels in primary LECs in response to any TLR ligand, and CCL21 was not expressed to detectable levels by the htert-HDLECs.…”

“…In addition, injection of TNF-␣ into skin can lead to increased expression of CCL21 by lymphatic vessels (16), although the mechanism of this induction is a matter of debate since in a later report, a pleiotropic cytokine, OSM, and not TNF-␣, directly enhanced expression of CCL21 by endothelial cells (24). Therefore, to understand better the effects of cytokines on LECs, we treated the three LEC populations with the cytokines IL-1␤, OSM, and TNF-␣ and measured changes in the expression of a subset of chemokines, cytokines, and adhesion molecules.…”

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

“…As OSM is also produced by Th1 cells and DC [5][6][7][8], OSM is suggested to play a role in immune reactions. In fact, OSM from activated DC regulates CCL21 expression in microvascular endothelial cells and promotes the trafficking of DC to LN [8].…”

Oncostatin M-Induced and Constitutive Activation of the JAK2/STAT5/CIS Pathway Suppresses CCL1, but Not CCL7 and CCL8, Chemokine Expression

“…In many cell types, OSM stimulation has also been reported to activate the MAPK ERK1/2 and the stress-activated protein kinases p38 and JNK (20 -22). These kinases have been implicated in the regulation of OSM-mediated chemokine expression in previous studies, i.e., eotaxin expression in fibroblasts, stromal-derived factor-1 in mesenchymal stem cells and CCL21 in microvascular endothelial cells (23)(24)(25).…”