| First Author | Lopez-Castejon G | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 4 | Pages | 2611-9 |
| PubMed ID | 20639492 | Mgi Jnum | J:162538 |
| Mgi Id | MGI:4819289 | Doi | 10.4049/jimmunol.1000436 |
| Citation | Lopez-Castejon G, et al. (2010) P2X7 Receptor-Mediated Release of Cathepsins from Macrophages Is a Cytokine-Independent Mechanism Potentially Involved in Joint Diseases. J Immunol 185(4):2611-9 |
| abstractText | The ATP-gated P2X(7) receptor (P2X(7)R) is a promising therapeutic target in chronic inflammatory diseases with highly specific antagonists currently under clinical trials for rheumatoid arthritis. Anti-inflammatory actions of P2X(7)R antagonists are considered to result from inhibition of P2X(7)R-induced release of proinflammatory cytokines from activated macrophages. However, P2X(7)Rs are also expressed in resting macrophages, suggesting that P2X(7)R may also signal via cytokine-independent mechanisms involved in joint disease. In this study, we examined P2X(7)R function in resting human lung macrophages and mouse bone marrow-derived macrophages and found that ATP induced rapid release of the lysosomal cysteine proteases cathepsin B, K, L, and S and that was independent of the presence of the proinflammatory cytokines IL-1beta and IL-18. Cathepsins released into the medium were effective to degrade collagen extracellular matrix. ATP-induced cathepsin release was abolished by P2X(7)R antagonists, absent from P2X(7)R(-/-) mouse macrophages, and not associated with cell death. Our results suggest P2X(7)R activation may play a novel and direct role in tissue damage through release of cathepsins independently of its proinflammatory actions via IL-1 cytokines. |
