Published ahead of print on May 5, 2005, doi:10.1165/rcmb.2005-0005OC Am. J. Respir. Cell Mol. Biol., Volume 33, Number 2, August 2005, 138-144 A more recent version of this article appeared on August 1, 2005
Submitted on January 5, 2005 The Effect of Cyclosporin A on Airway Cell Pro-Inflammatory Signaling and PneumoniaValerie Waters1,1 Department of Pediatrics and Pharmacology, Columbia University, New York, NY, USA * To whom correspondence should be addressed. E-mail: asp7{at}columbia.edu.
Cyclosporin A (CsA) blocks T cell activation by interfering with the Ca2+-dependent phosphatase, calciuneurin. Proinflammatory responses to bacteria that are activated by Ca2+-fluxes in the airway are a potential target for CsA. While local immunosuppression may be advantageous to control airway inflammation, it could also increase susceptibility to bacterial pneumonia and invasive infection. As aerosolized CsA is currently under study in lung transplantation, we examined its direct effects on airway cells as well as in a murine model of pneumonia. Epithelial IL-6 production was very effectively inhibited by CsA whereas CXCL8 production, the major PMN chemokine, was only modestly diminished. Responses to a TLR2 agonist Pam3Cys were more sensitive to CsA inhibition than those activated by P. aeruginosa. CsA substantially blocked NFAT and CREB activation (P<0.001), inhibited C/EBP by 50% (P<0.05) and minimally blocked AP-1 and NF-
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B responses to bacteria in epithelial cells. The in vitro effects were confirmed in a mouse model of P. aeruginosa infection with similar rates of PMN recruitment, pneumonia and mortality in CsA treated and control mice. These studies indicate that airway epithelial signaling is a potential target for CsA, and such local immunosuppression may not increase susceptibility to invasive infection.
