Is interleukin 17, an inducible cytokine that stimulates production of other cytokines, merely a redundant player in a sea of other biomolecules?

H 'ematopoiesis, the production of blood cells, is a dy~namic process, the regulation of which under normal conditions must be a tightly controlled process (1-7). Abnormalities in this process no doubt lead to acceleration of malignant and non-malignant disorders. It is over the last 40 yr that these normal and abnormal processes have begun to be unravelled and better defined. This is in large part due to the development of in vitro and in vivo assays that recognize and allow quantitation of different subsets o f hematopoietic stem and progenitor cells. Stem cells are defined as cells with multipotential lineage differentiation capacity and the ability to self-renew (make more cells o f their own kind). The earliest stem cells would be those with the greatest self-renewal capacity and would include the longterm marrow repopulating cell. Stem cells with less self-renewal and differentiation capacity exist and were originally defined by the in vivo spleen colony forming cell assay in mice. Progenitor cells are considered to have less self-renewal capacity, but the earliest subsets o f these can be multipotential. W e now know that hematopoiesis is regulated by an interacting network of cell-cell and cytokine-cell interactions (1-7). Hematopoiet ic stem and progenitor cells are influenced in their capacity to proliferate, differentiate, and possibly to self-renew, by accessory cell-derived biomolecules, most o f which can be classified as cytokines. It is only in the last 15 or so years that our knowledge of cytokines and their actions has blossomed. This is due to the recombinant D N A technology revolution that has allowed the identification, cloning and expression of an increasing number of genes for cytokines and their receptors. W e are at a stage where the in vitro actions o f cytokines which were first noted in the laboratory are rapidly translated into preclinical and clinical studies to assess the efficacy of these cytokines for potential clinical benefit (8-12). The most obvious of these translational efforts have been with the colony stimulating factors such as erythropoietin, granulocyte colony stimulating factor, granulocyte-macrophage colony stimulating factor, and most recently, thrombopoiet in. There are now over 50 bioactive molecules that are known to influence stem or progenitor cell proliferation and differentiation by stimulating, suppressing or enhancing the stimulation or suppression of these cells (1-7, 13). These effects can be direct on the stem or progenitor cells themselves, actions which are most rigorously determined in vitro with an initial culture of a single isolated stem or progenitor cell (14-16), or the effects can be indirectly mediated. This latter effect involves accessory cells which can be induced by a number of stimuli, including cytokines, to produce and release a single, but more likely a group of cytokines (1-7, 17-23) which can then directly act on stem or progenitor cells or have a cascading effect on induction of the production or release o f additional cytokines or other biologically active molecules. Accessory cells can be mature morphologically recognizable blood cells, such as lymphocytes (both T and B cells have been implicated although most is known about T cells), monocytes, macrophages and natural killer cells, or stromal cell elements such as fibroblasts, endothelial cells, epithelial cells, adipocytes and muscle cells (1-7, 17-23). A listing of biologically active molecules with known direct or indirect effects on stern and progenitor cell proliferation and differentiation is shown in Table 1 (1-7, 24-30). This listing is not meat to be all-inclusive as new cytokines are still being discovered. It is in this context that the article by Fossiez et al. (31) in this issue o f the Journal o f Experimental Medicine, which describes the cloning and action of expressed human IL-17, is o f interest. This study follows up on the cloning of murine IL-17 (cytotoxic T l y m p h o cyte-associated antigen-8, CTLA-8) (32) and complements the recent studies of Yao and colleagues regarding human lL-17 (33) and its novel receptor (34). Murine IL-17 was identified as part o f a search to detect novel molecules involved in functions of the immune system (32). This gene was found as a single copy in cells from mice, rats and humans and was mapped at a single site on mouse chromosome 1A and human chromosome 2q31. Murine IL-17 c D N A contained an opening reading frame that encoded a putative protein of 150 amino acids, which turned out to be 57% homologous to the putative protein encoded by the open reading frame (OILF) 13 gene o f a T l y m p h o tropic virus, herpesvirus Saimiri. This suggested another virus-captured gene with possible functional activity. A number of such virus-captured genes, hypothesized to be important for the residency of viruses in mammalian systems, have been previously reported (reviewed in references 31-34), including that o f IL-10, which has 70% homology with an EBV gene, BCRF1 (35). In the paper by