IL-6 is a typical example of a pleiotropic cytokine that acts on various cells: IL-6 induces the differentiation of B cells to antibody producing plasma cells, T-cell growth and differentiation, the differentiation of myeloid leukemic cell lines into macrophages, megakaryocyte maturation, the neural differentiation of PC12 cells, the development of osteoclasts, and acute-phase protein synthesis in hepatocytes. IL-6 acts as a growth factor for myeloma/plasmacytoma, keratinocytes, mesangial cells, renal cell carcinoma, and Kaposi's sarcoma, and promotes the growth of hematopoietic stem cells. In addition, IL-6 inhibits the growth of myeloid leukemic cell lines and certain carcinoma cell lines (see reviews 12, 20-24). In accordance with the multiple functions of IL-6, IL-6 transgenic mice or mice bearing a retrovirus vector expressing IL-6 show massive plasmacytosis, hypergammaglobulinemia, an increase in acute-phase proteins, mesangial proliferative glomerulonephritis, an increase in megakaryocytes (45,46), and eventually develop plasmacytoma (47). Based on the observations using IL-6 transgenic mice, together with the functional activity of IL-6 as a growth factor of myeloma and plasmacytoma, it was hypothesized that the deregulated expression of the IL-6 gene is involved in the generation of pristane-induced murine plasmacytoma and plays an important role in the development of myeloma in humans (48). In fact, it was shown using IL-6-deficient mice that IL-6 is essential for the development of plasmacytoma in vivo (49). IL-6 deficient mice showed a reduced IgG response, but no reduction in the IgM response to both a soluble protein antigen and vesicular stomatitis virus (VSV) antigen (50). A striking effect was observed in the mucosal IgA antibody response. In accordance with the original findings of Kiyono and McGhee and their colleagues (51,52) that IL-6 is involved in the IgA response, in IL-6 deficient mice, the number of IgA-producing cells was greatly reduced (53). This reduced IgA response was completely restored after intranasal infection with recombinant vaccinia viruses engineered to express IL-6. The generation of cytotoxic T cells against vaccinia virus was 3- to 10-fold reduced in IL-6 deficient mice, while CTL function against lymphocytic choriomeningitis virus (LCMV) was not reduced (50). Furthermore, the inflammatory acute-phase response after tissue damage or infection is severely compromised (50). An inability to clear Listeria monocytogenes was observed in IL-6 deficient mice (50,54). This inability is most likely due to the inability of neutrophils to function in IL-6 deficient mice, suggesting that IL-6 plays a critical role in listeriosis by stimulating neutrophils (54). Since an anti-IL-6 antibody can inhibit the increase in osteoclast precursors occurring in estrogen-depleted mice (55), and since estrogen can inhibit the IL-1- and TNFa-induced production of IL-6 (56), the overproduction of IL-6 has been suggested to be involved in the generation of postmenopausal osteoporosis. In support of this notion, ovariectomy does not induce any change in either bone mass or bone remodeling rates in IL-6 deficient mice, although estrogen deficiency induced by ovariectomy causes a significant loss of bone mass together with an increase in bone turnover rates in wild type mice (57). Intraperitoneal injections of either LPS or IL-1 beta failed to evoke a fever response in IL-6 deficient mice and the fever response was recovered by the intracerebroventricular injection of recombinant human IL-6, but not of IL-1, showing that IL-6 is a necessary component of the fever response to both IL-1 and LPS (58). These facts show that IL-6 is critical in only a limited range of biological reactions, such as the acute-phase response, the mucosal IgA response, the fever response, and estrogen deficiency-induced bone loss, although IL-6 has many biological activities. The biological activities of IL-6 may be compensated for by other cytokines showing functional redundancy with IL-6.
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