Importance of combined treatment with IL‐10 and IL‐4, but not IL‐13, for inhibition of monocyte release of the Ca2+‐binding protein MRP8/14

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Abstract
Expression of the two myeloic related proteins MRP8 and MRP14 is restricted to distinct stages of monocytic differentiation. Heterodimeric MRP8/14 complexes (27E10 antigen) have been shown to represent their biologically active forms. In this study, we investigated the effects of Th2‐cytokines on release of these proteins from freshly obtained blood monocytes and monocytes cultured for 7 days in the presence of granulocyte–macrophage colony‐stimulating factor (GM‐CSF). Monocytes were stimulated with pokeweed mitogen (PWM) in the presence or absence of interleukin‐13 (IL‐13), IL‐4 and IL‐10, and secretion of MRP8, MRP14 and MRP8/14 was assessed by using a sandwich enzyme‐linked immunosorbent assay system. Peripheral monocytes secreted significantly increased amounts of MRP14 and MRP8/14 but not MRP8 under stimulation with PWM. IL‐10 and IL‐4, but not IL‐13, down‐regulated the PWM‐stimulated MRP8/14 secretion in a dose‐dependent manner. Maximal inhibition required that IL‐10 and IL‐4 be added up to 1 h before or simultaneous with PWM. A combination of IL‐10 and IL‐4 even at suboptimal concentrations significantly suppressed protein secretion much more than using IL‐10 or IL‐4 at a doubled concentration alone. Peripheral monocytes cultured for 7 days in the presence of GM‐CSF showed two‐ to threefold higher protein levels compared with freshly obtained blood monocytes but responded inefficiently to either IL‐4, IL‐13, or IL‐10 alone. However, treatment with IL‐10 in combination with IL‐4 but not IL‐13 strongly suppressed MRP14 and MRP8/14 release by these cells. The unresponsiveness of 7‐day‐cultured blood macrophages suggests that more differentiated and activated cells may lose their ability to respond to anti‐inflammatory cytokines. Combined cytokine treatment may therefore more effectively control the progression of chronic inflammatory processes.

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