PMID- 20739459
OWN - NLM
STAT- MEDLINE
DCOM- 20110110
LR  - 20220316
IS  - 1460-2377 (Electronic)
IS  - 0953-8178 (Linking)
VI  - 22
IP  - 10
DP  - 2010 Oct
TI  - Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key 
      regulator of integrin-mediated dendritic cell transmigration.
PG  - 839-49
LID - 10.1093/intimm/dxq435 [doi]
AB  - Tissue inflammation induces rapid mobilization of antigen-charged dendritic cells 
      (DCs), which migrate to draining lymph nodes via afferent lymphatics to elicit 
      the immune response. This increase in DC trafficking has been shown to require 
      integrin-dependent adhesion to ICAM-1 and VCAM-1, expressed on inflamed lymphatic 
      endothelium. In addition, both constitutive- and inflammation-induced DC 
      migration involves the chemokine CCL21, which most likely triggers integrin 
      activation on DC via its receptor CCR7. Recently, however, conflicting evidence 
      has suggested that DC entry occurs independently of integrins, implying that the 
      role of CCL21 in lymphatics is purely chemotactic. Hence, while CCL21 is reported 
      to be inducible during inflammation, the details of this induction and the role 
      of CCL21 during initial DC trafficking are unclear. Here, we have characterized 
      both the production of CCL21 and the mechanism of its action in DC transmigration 
      using primary human dermal lymphatic endothelial cells (HDLECs) and a mouse model 
      of skin contact hypersensitivity. We showed that CCL21 is constitutively 
      expressed intracellularly but rapidly secreted after exposure to the inflammatory 
      cytokine tumour necrosis factor (TNF) alpha following de novo RNA and protein 
      synthesis. Furthermore, using in vitro transmigration assays, we showed that 
      endogenous HDLEC-derived CCL21 stimulates DC translymphatic migration by a 
      predominantly chemotactic mechanism in resting HDLEC and by a beta2 
      integrin-mediated mechanism in TNFalpha-stimulated HDLEC. These results imply a 
      direct role for CCL21 in lymphatic transmigration that involves the selective use 
      of integrin activation in inflammation.
FAU - Johnson, Louise A
AU  - Johnson LA
AD  - Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular 
      Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. 
      louise.johnson@imm.ox.ac.uk
FAU - Jackson, David G
AU  - Jackson DG
LA  - eng
GR  - G0801186/MRC_/Medical Research Council/United Kingdom
GR  - MC_U137884182/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100825
PL  - England
TA  - Int Immunol
JT  - International immunology
JID - 8916182
RN  - 0 (CD18 Antigens)
RN  - 0 (Chemokine CCL21)
SB  - IM
MH  - Animals
MH  - CD18 Antigens/*metabolism/pharmacology
MH  - Cell Movement/immunology
MH  - Cells, Cultured
MH  - Chemokine CCL21/*metabolism
MH  - Chemotaxis/immunology
MH  - Dendritic Cells/drug effects/*physiology
MH  - Dermatitis, Contact/immunology/metabolism
MH  - Disease Models, Animal
MH  - Endothelial Cells/immunology/metabolism
MH  - Endothelium, Lymphatic/immunology/*metabolism
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Inflammation/*immunology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Skin/cytology/immunology/metabolism
EDAT- 2010/08/27 06:00
MHDA- 2011/01/11 06:00
CRDT- 2010/08/27 06:00
PHST- 2010/08/27 06:00 [entrez]
PHST- 2010/08/27 06:00 [pubmed]
PHST- 2011/01/11 06:00 [medline]
AID - dxq435 [pii]
AID - 10.1093/intimm/dxq435 [doi]
PST - ppublish
SO  - Int Immunol. 2010 Oct;22(10):839-49. doi: 10.1093/intimm/dxq435. Epub 2010 Aug 
      25.