Prostaglandin E2-Dependent Enhancement of Tissue Inhibitors of Metalloproteinases-1 Production Limits Dendritic Cell Migration through Extracellular Matrix

Abstract

Dendritic cell (DC) migration is crucial for the initiation of immune responses. The balance between metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) has been shown to modulate DC migration. PGE2, which is overproduced in a wide variety of human malignancies, has been implicated in MMP and TIMP regulation in various cells, including monocytes. In the present study, we hypothesized that tumor-derived PGE2 would affect DC migratory capacity through the extracellular matrix (ECM) by altering MMP and TIMP balance. Treatment of monocyte-derived immature DC with exogenous PGE2 induced TIMP-1 secretion but not MMP-9 production and was correlated with reduced DC migration through ECM. Because recombinant TIMP-1 replicated PGE2 inhibition of DC migration while anti-TIMP-1 neutralizing Ab reversed it, we conclude that PGE2-mediated induction of TIMP-1 was responsible for the reduced migration of PGE2-treated DC. Similarly, DC cultured for 48 h in supernatants from cyclooxygenase-2 overexpressing lung cancer cells that secrete high levels of PGE2, exhibited decreased migration through ECM. Finally, analysis of E prostanoid receptor expression and their selective inhibition revealed that the enhanced TIMP-1 secretion in PGE2-treated DC was mediated predominantly by the E prostanoid receptor 2. These findings indicate that PGE2-dependent enhancement of TIMP-1 production causes reduced migration of DC through ECM.

Cyclooxygenase-2 and tissue inhibitor of matrix metalloproteinases-1 confer the antimigratory effect of cannabinoids on human trabecular meshwork cells

“…Upregulation of TIMP-1 expression by cannabinoids has also been demonstrated in cervical carcinoma and lung cancer cells [48], albeit a possible COX-2-dependent pathway was not focussed on in these cells. Moreover, the antimigratory function 21 of TIMP-1 shown here is in line with other studies demonstrating a correlation between increased TIMP-1 levels and impaired cellular migration [47,[49][50][51][52][53].…”

“…A relationship between COX-2 and TIMP-1 has also been established in other cell types. In support of the data presented here, an upregulation of TIMP-1 expression by COX-2-dependent PGs has been observed in human monocytes [46], human dendritic cells [47] and human non-pigmented ciliary epithelial cells [11]. In the latter cell type, cannabinoids elicited increased expression of TIMP-1 along with that of MMP-9 via a mechanism requiring prior induction of COX-2 [11].…”

Translocation of Active Heparanase to Cell Surface Regulates Degradation of Extracellular Matrix Heparan Sulfate upon Transmigration of Mature Monocyte-Derived Dendritic Cells

“…However, to migrate from peripheral tissue such as the epidermis to regional lymph nodes, Ag-bearing epidermal Langerhans cells must move through an extracellular matrix (ECM) of various compositions. The nature of their capacity to transmigrate via the ECM, which is only partially understood, is affected by matrix metalloproteinases (MMPs) and MMP inhibitors, as well as PGE 2 and other inducers of MMP inhibitors (3)(4)(5). We wanted to verify whether heparanase, a heparan sulfate-degrading endoglycosidase that participates in ECM degradation and remodeling, is expressed and functional in monocyte-derived DCs.…”

Prostaglandin E2 Induces FOXP3 Gene Expression and T Regulatory Cell Function in Human CD4+ T Cells

“…Cell purity assessed by flow cytometry was Ն92%. Before being used in different experimental conditions, purified CD4 ϩ CD25 ϩ and CD4 ϩ CD25 Ϫ T cell fractions were preincubated for 24 h in X-Vivo 15 (BioWhittaker), 10% FBS, and 1% human serum AB (Gemini) (24) with or without 16,16-dimethyl-PGE 2 (Cayman Chemical; 13 or 26 M). In some experiments, CD4 ϩ CD25 Ϫ T cells (2 ϫ 10 6 ) were preincubated for 18 -24 h with 2 ml of undiluted tumor supernatant obtained from H157 (human squamous cell carcinoma; American Type Culture Collection) NSCLC, genetically modified to express COX-2 sense (S), COX-2 antisense (AS), or control empty vector (CV) (25).…”