Microenvironmental Control of Inflammatory Cell Differentiation

A wide body of information now exists on hemopoietic and proinflammatory cytokine production by structural cells of the microenvironment. Included among these are epithelial cells, endothelial cells and fibroblasts which can, either constitutively or upon stimulation with other cytokines or lipopoly-saccharide, express the genes for, and produce, IL-6, IL-8, G-CSF, GM-CSF, and M-CSF, as well as yet unidentified cytokines with prominent cell differentiation-inducing activities. Inflammatory cells which accumulate at sites of allergic-type reactions include granulocytes such as basophils, eosinophils and mast cells, as well as neutrophils and cells of the monocyte-macrophage lineage. Combinations of cytokines produced by tissue structural cells have been studied with reference to their capacity to induce differentiation, activate and prolong the survival of inflammatory cells. Evidence can be adduced for the differentiation process being intimately connected to phenotype switch and activation of cells, such as eosinophils and mast cells, which themselves can feed back upon this by production of cytokines such as TGF-β and GM-CSF; the production of T cell-derived cytokines such as IL-3, IL-5 and GM-CSF can be shown to contribute to basophil and eosinophil differentiation and activation. Work from our laboratory will be summarized with reference to the syntax and language of structural cell-derived cytokines in terms of inflammatory cell differentiation pathways, using a variety of in vitro and in vivo detection techniques. Application of these findings to the control of inflammatory reactions as well as wound repair will also be discussed.