Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21.
Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is the severest form of idiopathic interstitial pneumonia for which therapeutic targets are needed. Surgical lung biopsy specimens from IPF/UIP patients exhibit focal expression of CC chemokine receptor (CCR) 7, but the identity of these CCR7-positive cells is unknown. The purpose of the present study was to examine the functional and signalling significance of CCR7 expression of primary fibroblasts grown from IPF/UIP and normal surgical lung biopsy specimens. Primary fibroblasts were cultured from surgical lung biopsy specimens from IPF/UIP and normal patients. Fibroblasts treated with or without CC chemokine ligand (CCL) 21 were analysed for functional, transcriptional and proteomic differences using immunocytochemical analysis, gene arrays, Taqman real-time PCR, and migration, proliferation and Western blot assays. CCR7 was expressed by IPF/UIP fibroblasts, but not normal fibroblasts. IPF/UIP fibroblasts, but not normal fibroblasts, showed significant migratory and proliferative responses when exposed to CCL21, which were inhibited by pertussis toxin or neutralising antibodies to CCR7. Exposure of IPF/UIP fibroblasts to CCL21 altered the phosphorylation status of mitogen-activated protein kinase kinase 1/2, extracellular signal-regulated kinase 1/2 and ribosomal S6 kinase (90 kDa) in these cells; this was abrogated by pertussis toxin or CCR7-specific small interfering RNA. Together, these data demonstrate that CC chemokine ligand 21 modulates the functional properties of idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblasts, but not normal fibroblasts.
Pierce
E M
EM
Immunology programme, Department of Pathology, University of Michigan Medical School, Room 4057, BSRB, 109 Zina Pitcher Place, Ann Arbor MI 48109-0602, USA.
Carpenter
K
K
Jakubzick
C
C
Kunkel
S L
SL
Evanoff
H
H
Flaherty
K R
KR
Martinez
F J
FJ
Toews
G B
GB
Hogaboam
C M
CM
D001706:Biopsy; D002465:Cell Movement; D049109:Cell Proliferation; D054421:Chemokine CCL21; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D008168:Lung / Q000473:pathology; D011014:Pneumonia / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology*; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism
C515478:CCL21 protein, human; C483024:CCL5 protein, human; C515370:CCR7 protein, human; D054421:Chemokine CCL21; D018946:Chemokine CCL5; D019742:Chemokines, CC; D008024:Ligands; D054400:Receptors, CCR7; D019707:Receptors, Chemokine