The biology of interleukin-6.

B CELLS ARE the only eukaryotic cells that are able to produce antibody molecules. Their growth and differentiation into antibody producing cells require the presence of T cells and macrophages; the function of these cells was found to be replaced by soluble factors. 3 In the early i980s it was shown that at least two different kinds of factors were required in the regulation of B cell response, one for growth of activated B cells, B-cell growth factor (BCGF), and the other for antibody induction in B cells, B-cell differentiation factor (BCDF). 6 Since then, a variety of factors regulating the B cell response have been reported in the human and murine systems. Finally, in 1986 the cDNAs for three B-cell stimulatory factors have been cloned; interleukin-4 (IL-4) (BCGF1 /BSF1 ) for the early activation of resting B cells,7’8 IL-5 (BCGFII) for the growth ofactivated B cells,9 and IL-6 (BCDF/BSF2) for the final differentiation of B cells into antibody producing cells’#{176} (Fig 1). Human IL-6 (BSF2) was originally identified as a factor in the culture supernatants of mitogen or antigen-stimulated peripheral mononuclear cells, which induced immunoglobulin production in Epstein Barr virus (EBV) transformed B-cell lines or in Staphylococcus aureus Cowan 1 (SAC) stimulated normal B cells.t1 This molecule was found to be separable from other factors, such as IL-2 and BCGFs, and the establishment of human T cell hybridoma generating BSF2 activity confirmed that this is a distinct molecule from other cytokines.6 BSF2 was purified to homogeneity from the culture supernatant of a human T-cell leukemia virus type 1 (HTLV1 ) transformed T-cell line and its partial N-terminal amino acid sequence was determined.t2 Based on these findings, the cDNA encoding human BSF2 was cloned. #{176} Approximately at the same time, the molecular cloning and the nucleotide sequences of the molecules termed interferon / 2 (IFN 32)’3 and 26 Kd protein were reportedt4 and the results revealed that BSF2, IFN 32, and 26 Kd protein were identical. In I 980, an inducible mRNA species of about 1 3S encoding for a novel human fibroblast-type interferon (IFN), named 1FNf32 was reported.’5 The isolated cDNA clone for such an induced mRNA was trancribed in vitro into a protein of 26 Kd. One group detected an antiviral activity that was neutralized with anti-IFNf 2 and thus called this molecule IFNj32)5 On the other hand, another group could not detect any antiviral activity in this protein’6 and its interferon activity was controversial until recombinant molecules became available. In 1987 recombinant IL-6 (r IL-6) was shown to have no IFN activity and to have antigenically and functionally no relations with IFNfl.’7 Growth factors for plasmacytomas/myelomas have been reported by several investigators.’8’20 In 1 986, N-terminal amino acid sequence of a human cytokine that showed hybridoma/plasmacytoma growth factor activity was determined and the result again showed that the factor was identical with BSF2/IFN/32/26 Kd protein.2’ Subsequently, the cDNA cloning of murine hybridoma/plasmacytoma growth factor was completed and the sequence indicated that it was the murine homologue of IL-6/BSF2.2223 Therefore, all the results demonstrated that IL-6 has the growth activity in plasmacytoma/myeloma cells. The other major activty of IL-6 is induction of acute phase proteins in hepatocytes. The studies with IL-6 and anti-IL-6 antibody carried out by Gauldie et a124 and Andus et a125 clearly demonstrated that IL-6 functioned as a hepatocyte stimulating factor (HSF) and induced the production of major acute phase proteins. As described, the molecular cloning of the cDNA of IL-6 indicated that the function of IL-6 is not restricted to B lineage cells but shows a wide variety of biological activities on various tissues and cells. Table 1 summarizes the activities exerted by molecules identified to be identical to IL-6.