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Published ahead of print on October 13, 2005, doi:10.1165/rcmb.2005-0126OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 233-241, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0126OC

Neutrophil Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors in Pneumonia

Matiur Rahaman, Richard W. Costello, Kristen E. Belmonte, Samir S. Gendy and Marie-Thérèse Walsh

Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland; and Respiratory and Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania

Correspondence and requests for reprints should be addressed to Marie-Thérèse Walsh, Department of Medicine, RCSI, Beaumont Hospital, Dublin 9, Ireland. E-mail: mtwalsh{at}rcsi.ie

The phospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) act via transmembrane receptors S1P 1–5 and LPA 1–3, respectively. Both have been implicated in inflammatory responses. S1P and LPA receptor profiles on neutrophils of patients with pneumonia compared with healthy subjects were determined by PCR and Western blotting. Chemotaxis studies were performed to assess functional differences. S1P or LPA receptors were immunoprecipitated from neutrophils to assess receptor heterodimerization with CXCR1, an IL-8 receptor, by Western blotting. Receptors S1P 1, 4, and 5 and LPA 2 were expressed on neutrophils from both subject groups, but S1P 3 and LPA 1 receptor expression was mainly confined to neutrophils of patients with pneumonia. Chemotaxis of neutrophils from patients with pneumonia compared with control subjects was significantly increased in response to S1P and LPA. Pretreatment with S1P or LPA reduced IL-8–induced neutrophil chemotaxis and transcriptional expression of the CXCR1 receptor. Receptors S1P 3 and 4 and LPA 1 formed constitutive heterodimers with CXCR1. LPA treatment reduced the amount of LPA 1/CXCR1 heterodimer. Therefore, profiles of S1P and LPA receptors differ between neutrophils of patients with pneumonia and control subjects, with consequences for neutrophil function.

Key Words: heterodimerization • lysophosphatidic acid • neutrophils • receptor • sphingosine 1-phosphate




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