Cytokine regulation of IL-1β gene expression in the human polymorphonuclear leukocyte

Although recently polymorphonuclear leukocytes (PMN) have been identified as producers of IL-1β in response to LPS and granulocyte/monocyte colony stimulating factor, little is known regarding the ability of other cytokines to induce the production of IL-1β in the PMN. Inasmuch as IL-1 and TNF have been shown to be important priming agents, as well as agents that induce migration of PMN, we investigated their effect on IL-1β gene expression in human peripheral blood PMN. In the present study, we demonstrate that human peripheral blood PMN produce IL-1β in response to IL-1α, IL-1β, and TNF-α. Control (unstimulated) human PMN had virtually undetectable levels of IL-1β mRNA. Either IL-1β or TNF, induced PMN to transiently express IL-1β mRNA with peak expression at 1 h, returning to untreated levels by 2 h. A dose response indicated that as little as 0.05 ng/ml of IL-1β or TNF resulted in IL-1β induction, with maximal effects at 1 ng/ml of IL-1β and 5 ng/ml of TNF. IL-1α or IL-1β exhibited similar dose responses in IL-1β mRNA induction. Inasmuch as cytokines have been shown to have synergistic effects in cell function studies, we induced PMN with a combination of maximally effective doses of TNF plus IL-1β. They demonstrated a cooperative effect on IL-1β gene expression, in that mRNA levels were sustained for three hours. IL-1β Ag expression, as measured by ELISA, paralleled IL-1β mRNA expression with cell associated peak levels at 2 to 4 h. IL-1β Ag levels in PMN lysates and supernatants correlated with IL-1β mRNA levels, i.e., TNF + IL-1 > TNF > IL-1. Thus, these studies represent the first demonstration of IL-1 and TNF induction of IL-1β gene expression in the PMN. Furthermore, the time course of induction is unique to the PMN, with peak induction of mRNA at 1 h, which is consistent with the short lived nature of these cells in inflammatory lesions.