The effect of cyclosporin A on airway cell proinflammatory signaling and pneumonia.

Abstract

Cyclosporin A (CsA) blocks T cell activation by interfering with the Ca2+-dependent phosphatase, calcineurin. Proinflammatory responses to bacteria that are activated by Ca2+-fluxes in airway cells are a potential target for CsA. Although 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 interleukin-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 Pseudomonas aeruginosa. CsA substantially blocked activation of nuclear factor of activated T cells and cAMP-responsive element-binding protein (P<0.001), inhibited CCAAT/enhancer-binding protein by 50% (P<0.05), and minimally blocked activator protein-1 and nuclear factor-kappaB 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.

• Authors: Valerie Waters, Sach Sokol, Bharat Reddy, Grace Soong, Jarin Chun, Alice Prince
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 33 Issue 2 Pg. 138-44 (Aug 2005) ISSN: 1044-1549 [Print] United States
• PMID: 15879161 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chemokines, CXC
• Immunosuppressive Agents
• Inflammation Mediators
• Interleukin-6
• Cyclosporine

Topics

• Administration, Inhalation
• Animals
• Calcium Signaling
• Cell Line
• Chemokines, CXC (biosynthesis)
• Cyclosporine (administration & dosage, pharmacology, toxicity)
• Humans
• Immunosuppressive Agents (administration & dosage, pharmacology, toxicity)
• Inflammation Mediators (metabolism)
• Interleukin-6 (biosynthesis)
• Mice
• Mice, Inbred BALB C
• Pneumonia, Bacterial (immunology, pathology)
• Pseudomonas Infections (immunology, pathology)
• Pseudomonas aeruginosa (pathogenicity)
• Respiratory System (drug effects, immunology, pathology)
• Signal Transduction (drug effects)