Mononuclear phagocytes are essential cellular mediators of both acute and chronic inflammatory responses. In addition to producing substances that mediate tissue injury directly, such as proteolytic enzymes and oxygen radical species, mononuclear phagocytes can secrete proteins involved in the activation and recruitment of inflammatory cells. One of the major inducible polypeptides secreted by mononuclear phagocytes is macrophage inflammatory protein 1 (MIP-1). Native MIP-1 is a protein with leukocyte chemotactic and stimulatory activity. MIP-1 consists of two highly homologous peptides, MIP-1α and MIP-1β. We now characterize the expression of MIP-1α from human peripheral blood monocytes (PBM) and identify the T-lymphocyte product interleukin-4 (IL-4) as an important regulator of MIP-1α expression from PBM. In initial experiments, we demonstrated the production of MIP-1α from lipopolysaccharide (LPS)-, interleukin-1 (IL-1)-, and phytohemagglutinin (PHA)-stimulated PBM. IL-4 inhibited the production of MIP-1α from 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-1α mRNA, which was reduced in a dose-dependent fashion by IL-4. The suppression of MIP-1α mRNA by IL-4 was observed within a narrow temporal window and was dependent upon the de novo synthesis of a protein intermediate. As determined by mRNA stability studies, IL-4 decreased steady-state levels of MIP-1α mRNA, in part, by accelerating MIP-1α mRNA decay. Human alveolar macrophages (AM), which represent a more terminally differentiated mononuclear phagocyte population, also produce MIP-1α when challenged with LPS. The production of MIP-1α from AM was similarly inhibited by IL-4. Our findings indicate that IL-4 is an important endogenous regulator of MIP-1α gene expression from human PBM and AM, and that IL-4 may function in vivo as an important downregulator of acute inflammatory responses.