Up-regulation of Interleukin-8, Interleukin-10, Monocyte Chemotactic Protein-1, and Monocyte Chemotactic Protein-3 in Peripheral Blood Monocytes in Stable Lung Transplant Recipients: Are Immunosuppression Regimens Working?

Abstract

<h4>Background</h4>Alveolar macrophages are a major source of inflammatory cytokines and chemokines involved in the pathogenesis of lung transplant rejection and are derived from blood monocytes that migrate to the lung. Levels of monocyte cytokines and chemokines that may be relevant in transplant rejection have not previously been determined in transplant recipients. We hypothesized that production of these inflammatory mediators by blood monocytes may be up-regulated despite the use of potent immunosuppression therapy.<h4>Method</h4>To investigate this, whole blood from 9 stable lung transplant recipients and 12 control volunteers was stimulated with lipopolysaccharide in vitro, and intracellular chemokine and cytokine production were determined with multiparameter flow cytometry.<h4>Results</h4>Monocyte production of chemokines interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, and MCP-3, and anti-inflammatory cytokine IL-10 were significantly increased in the lung transplant group, but IL-6, tumor necrosis factor-alpha, IL-1alpha, IL-12, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, and transforming growth factor-beta levels were unchanged.<h4>Conclusions</h4>Because MCP-3 is a major chemoattractant for leukocytes to sites of antigenic challenge and is a natural ligand for MCP-1 receptor, this novel finding has important implications for the pathogenesis of lung transplant rejection. We now provide evidence that current immunosuppression protocols have a limited effect on monocyte inflammatory cytokine production and do not adequately suppress monocyte IL-8, MCP-1, and MCP-3 chemokine production. Drugs that modulate the action of these chemokines may improve current protocols for reducing graft rejection. Intracellular chemokine and cytokine analysis with flow cytometry may be a more accurate indicator of immunosuppression than drug levels in these patients.