Numerous studies investigating interleukin-6 (IL-6) expression in zyxwvutsrqpon pitvt, have revealed that zyxwvutsrqponmlk this multifunctional cytokine can be synthesized and secreted by many different cell-types. Endothelial cells lining the vasculature1. 2 as well as the underlying vascular smooth muscle cells3 can produce copious amounts of IL-6 when appropriately stimulated. In the blood, monocyte~~.~ as well as B-cells6 can also secrete significant amounts of IL-6. In every tissue that has been studied cells producing IL-6 have been found, including fib~ oblasts,~ endometrial stromal cells,'normal keratinocytes: pancreatic islet cells: osteoclasts, lo astrocytes and Virtually every type of tissue rnacrophage.". l2 In fact only normal human T-cells seem to distinguish themselves by their inability or, at best, poor facility to express IL-6. l3 Paradoxically it was a T-cell line from which IL-6 was cloned as a B-cell differentiation factor (Bcdf), and on this basis it was originally suggested that Bcdf is a T-cell replacement factor. 14 Now it is clear that IL-6 can be produced in virtually every tissue in the body and the range of celltype-specific inducers is extensive and includes IL-la, IL-lP, TNF-0, lymphotoxin, interferons, IL-2, IL-4, IL-11, all types of viruses (single or double-stranded RNA or DNA), bacterial products (Gram negative or positive-derived) lipopolysaccharide (LPS) and muramyl dipeptides and virtually every recognized second messenger agonistI2 IL-6 promoter dissections have revealed multiple res nse elements consistent

In 1992 we demonstrated that IL-6 is a normally circulating plasma protein. 16 Despite all of the intriguing cell-specific regulation of IL-6 gene expression, it became clear that there was always a significant level of IL-6 in blood (210 nanograms/ml). However, this circulating IL-6 was completely camouflaged from the routine IL-6 bioassay, the B9 cell-growth-factor assay. Furthermore, this endogenous IL-6 found in serum or plasma was essentially transparent to all of the customary enzyme-linked immunosorbent assay (ELISA). Thus, we could identify as much as 5 pg/d of IL-6 (confirmed by amino acid analysis) in serum or plasma that scored less than 200 picograms/ml in a commercially available ELISA and less than 50 picogramdml by B9 cell zyxwvutsrqponmlkji