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Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21

¹ Dept of Pathology, and ² Division of Pulmonary and Critical Care Medicine, Dept of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

CORRESPONDENCE: C. M. Hogaboam, Immunology programme, Dept of Pathology, University of Michigan Medical School, Room 4057, BSRB, 109 Zina Pitcher Place, Ann Arbor MI, 48109-0602, USA. Fax: 1 7349367996. E-mail: Hogaboam{at}med.umich.edu

Keywords: CC chemokine ligand 21, CC chemokine receptor 7, chemokine, idiopathic interstitial pneumonia, mitogen-activated protein kinase, pulmonary

Received: September 19, 2006
Accepted February 9, 2007

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.