This laboratory has focused its efforts on the biochemical characterization of the effects of IL 1 on target cells. Specifically, we have been analyzing the control of IL 1 receptor expression and the intracellular events which occur after IL 1 treatment of target cells. We have previously reported the existence of interleukin 1 (IL 1) receptors on EBV transformed human B lymphocytes, and the identity of the receptor for IL 1 alpha and IL 1 beta. We also determined that IL 1 receptor expression is rapidly down-regulated after IL 1 stimulation with internalization of the radiolabeled IL 1. We have now investigated factors that regulate IL 1 receptor expression. These studies have revealed that glucocorticoids and prostaglandins up- regulate IL 1 receptor expression on human B lymphocytes and fibroblasts. We have established the functionality of glucocorticoid induced IL 1 receptor on B cells by showing that IL 1 induces considerable protein phosphorylation at serine residues of a 65 kDa cytosolic protein in glucocorticoid treated human peripheral blood mononuclear cells (PBMC). This 65 kDa protein, whose phosphorylation is selectively augmented by IL 1 stimulation in PBMC, has been purified to homogeniety and the amino acid sequence indicates that this 65 kDa protein is a novel protein. We have also been studying the mechanism of the cytostatic/cytocidal effect of IL 1 on several types of tumor cell lines. We have observed that IL 1 synergizes with TNF and type I IFN in inducing terminal differentiation of the myelocytic M1 cell line into macrophages. We have also found that IL 1 selectively stimulates the production of a 25 kDa mitochondrial protein in A375 cells while being inhibited from growing by IL 1. The biochemical purification and amino acid sequence of this 25 kDa protein revealed that the 25 kDa protein is manganese type superoxide dis-mutase, suggesting the involvement of superoxide generation in tumor killing by IL 1. The better understanding of the regulation of IL 1 receptor expression and mechanism of IL 1 cytotoxicity should enable us to use IL 1, as a BRM, more effectively.
