GENE-EXPRESSION OF MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA FROM HUMANBLOOD MONOCYTES AND ALVEOLAR MACROPHAGES IS INHIBITED BY INTERLEUKIN-4

Mononuclear phagocytes are essential cellular mediators of both acute and chronic inflammatory responses. In addition to producing substance s that mediate tissue injury directly, such as proteolytic enzymes and oxygen radical species, mononuclear phagocytes can secrete proteins i nvolved in the activation and recruitment of inflammatory cells. One o f the major inducible polypeptides secreted by mononuclear phagocytes is macrophage inflammatory protein 1 (MIP-1). Native MIP-1 is a protei n with leukocyte chemotactic and stimulatory activity. MIP-1 consists of two highly homologous peptides, MIP-1alpha and MIP-1beta. We now ch aracterize the expression of MIP-1alpha from human peripheral blood mo nocytes (PBM) and identify the T-lymphocyte product interleukin-4 (IL- 4) as an important regulator of MIP-1alpha expression from PBM. In ini tial experiments, we demonstrated the production of MIP-1alpha from li popolysaccharide (LPS)-, interleukin-I (IL-1)-, and phytohemagglutinin (PHA)-stimulated PBM. IL-4 inhibited the production of MIP-1alpha fro m LPS-, IL-1-, and PHA-challenged PBM by 63, 81, and 88%, respectively . The suppressive effects of IL-4 were operative at the level of MIP-1 alpha mRNA, which was reduced in a dose-dependent fashion by IL-4. The suppression of MIP-1alpha mRNA by IL-4 was observed within a narrow t emporal window and was dependent upon the de novo synthesis of a prote in intermediate. As determined by mRNA stability studies, IL-4 decreas ed steady-state levels of MIP-1alpha mRNA, in part, by accelerating MI P-1alpha mRNA decay. Human alveolar macrophages (AM), which represent a more terminally differentiated mononuclear phagocyte population, als o produce MIP-1alpha when challenged with LPS. The production of MIP-1 alpha from AM was similarly inhibited by IL-4. Our findings indicate t hat IL-4 is an important endogenous regulator of MIP-1alpha gene expre ssion from human PBM and AM, and that IL-4 may function in vivo as an important downregulator of acute inflammatory responses.