The biology of interleukin-6.

When stimulated with antigen, B cells are influenced by T cells to proliferate and differentiate into antibody-forming cells. Since it was reported that soluble factors could replace certain functions of helper T cells in the antibody response, several different kinds of lymphokines and monokines have been reported in B-cell growth and differentiation. Among these, human B-cell differentiation factor (BCDF or BSF-2) has been shown to induce the final maturation of B cells into immunoglobulin-secreting cells. BSF-2 was purified to homogeneity and its partial NH2-terminal amino-acid sequence was determined. These studies indicated that BSF-2 is functionally and structurally unlike other known proteins. Here, we report the molecular cloning, structural analysis and functional expression of the cDNA encoding human BSF-2. The primary sequence of BSF-2 deduced from the cDNA reveals that BSF-2 is a novel interleukin consisting of 184 amino acids.

Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin

We have identified and purified a novel cytokine, NK cell stimulatory factor (NKSF), from the cell-free supernatant fluid of the phorbol diester-induced EBV-transformed human B lymphoblastoid cell line RPMI 8866. NKSF activity is mostly associated to a 70-kD anionic glycoprotein. The purified 70-kD protein, isolated from an SDS-PAGE gel, yields upon reduction two small species of molecular masses of 40 and 35 kD, suggesting that this cytokine is a heterodimer. When added to human PBL, purified NKSF preparations induce IFN-gamma production and synergize with rIL-2 in this activity, augment the NK cell-mediated cytotoxicity of PBL preparations against both NK-sensitive and NK-resistant target cell lines, and enhance the mitogenic response of T cells to mitogenic lectins and phorbol diesters. The three activities remain associated through different purification steps resulting in a 9,200-fold purification, and purified NKSF mediates the three biological activities at concentrations in the range of 0.1-10 pM. These data strongly suggest that the same molecule mediates these three activities, although the presence of traces of contaminant peptides even in the most purified NKSF preparations does not allow us to exclude the possibility that distinct biologically active molecules have been co-purified. The absence of other known cytokines in the purified NKSF preparations, the unusual molecular conformation of NKSF, the high specific activity of the purified protein, and the spectrum of biological activities distinguish NKSF from other previously described cytokines.

https://rupress.org/jem/article-pdf/170/3/827/1099552/827.pdf

Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes.

结节病易误诊,据王洪武等~([1])收集国内18篇关于此病误诊的文献,误诊率高达63.2%,当然有误诊就会有误治,如孙永昌等~([2])报道26例结节病在影像学检查诊断的第一印象中拟诊结核5例,其中就有2例完成规范的抗结核治疗,为此应引起临床对本病诊治的重视。

Sarcoidosis

Publisher Summary This chapter focuses on structure and expression of interleukin-6 (IL-6), which is a cytokine with pleiotropic activities that plays a central role in host defense. IL-6 can exert growth-inducing, growth-inhibitory, and differentiation-inducing activities, depending on the target cells. These activities include (1) terminal differentiation (secretion of immunoglobulins) in B cells and (2) growth promotion on various B cells. IL-6 has been implicated in the pathology of many diseases including multiple myeloma, mesangial proliferative glomerulonephritis, rheumatoid arthritis, and acquired immunodeficiency syndrome (AIDS). Selective inhibition of the synthesis or of the action of IL-6 may have therapeutic benefit against the IL-6-associated diseases. On the other hand, IL-6 has potent antitumor activity against certain types of tumors. Application of IL-6 is promising in cancer treatment as well as in treatment of radiation- or chemotherapy-induced myelosuppression. The cell biology of the intracellular events that link transduction to gene regulation is an important area, and work on these topics helps to understand such phenomena as multifunction of IL-6 and bidirectional effects of cell growth depending on the cell type.

Interleukin-6 in biology and medicine

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1016/0014-5793%2889%2980805-1

Interleukin‐6 (IL‐6) functions as an in vitro autocrine growth factor in renal cell carcinomas

IgG-secretion was induced in a human B blastoid cell line, CESS, by the addition of partially purified T cell-derived helper factor(s) (TRF), which had been obtained from PHA-stimulated human T cells. The number of IgG-producing cells in CESS cells reached its maximal level (10% of total cells) within 48 hr after the addition of TRF. TRF did not affect the proliferation of CESS cells and the block of cell proliferation with hydroxyurea did not inhibit the increase of IgG-producing cells, showing that TRF induced IgG-production in CESS cells without any requirement of cell division. TRF activity was completely removed by CESS cells but TCGF-activity in the same preparation was not absorbed with CESS cells. On the other hand, TCGF-dependent human killer cells absorbed TCGF activity but not TRF activity in the same preparation. The binding of 125I-labeled factor(s) on CESS cells was also demonstrated. These results showed the presence of acceptors for TRF on the surface of CESS cells and this cell line will provide useful means for the chemical characterization of acceptors and for the study of the mechanisms of the signal transmission through acceptors.

T cell-replacing factor- (TRF) induced IgG secretion in a human B blastoid cell line and demonstration of acceptors for TRF.

B cells, one of the best understood eukariotic cells, originate from pluripotent hematopoietic stem cells and differentiate into immunoglobulin {Ig)-secreting cells through multistep developmental stages, such as pre-pre-B cells, pre-B cells, immature B cells, mature B cells, activated B cells and Ig-secreting cells. An understanding of the stimuli which cause the activation, proliferation and differentiation of B cells is critical to the delineation of the normal regulation of the immune responses as well as proliferation and differentiation of eukariotic cells. Since the discovery of T-B collaboration in the antibody response, extensive studies on the regulatory molecules involved in B cell activation have been done. More than a decade ago, Dutton and his colleagues (1971) suggested the involvement of soluble helper factors in the T cell-dependent activation of B cells into Ig-secreting cells. Since then, hundreds of factors, antigen specific or nonspecific, have been reported and those results have supported the notion that helper or suppressor function of T cells in B cell activation can be replaced by the soluble products released from T cells. Kishimoto and Ishizaka (1975) and Kishimoto and his colleagues (1975) have shown Ig-induction in rabbit B cells by anti-Ig and T cell-derived helper factors, suggesting that 2 signals, crosslinkage of Ig-receptors and helper factors, could induce activation of B cells into Igproducing cells. This finding was confirmed by several investigators in murine or human B cells (Parker etal. 1979, Isakson etal. 1981, Yoshizaki et al. 1982)and also supported the notion that helper function of T cells was mediated by T cellderived helper factors.

B cell growth and differentiation factors and mechanism of B cell activation.

Stimulation of human B lymphoblastoid cell lines, CESS and SKW6-CL4 with BCDF induced an increase in IgG- and IgM-secreting cells, as well as a slight increase in IgG and IgM expression on their respective surfaces. Biosynthetic labeling demonstrated that BCDF stimulation induced an increase in synthesis of secretory gamma- and mu-chains, as well as their precursors. A slight but significant increase in synthesis of membrane-bound gamma- and mu-chains and their precursors was also observed by BCDF stimulation. However, an increase in synthesis of secretory heavy chains was much higher than that in membrane-bound heavy chains in both cell lines. Pulse-chase experiments showed that increased synthesis of secretory heavy chains was not due to a decrease in degradation. BCDF stimulation induced a preferential increase in mRNA specific for secretory gamma- and mu-chains in CESS and SKW6-CL4 cells, respectively. These results suggest that BCDF induces an increase in the level of mRNA specific for secretory heavy chains, and then induces final maturation of B cells into immunoglobulin-secreting cells.

Y Miki

Papers

Interleukin‐6 (IL‐6) functions as an in vitro autocrine growth factor in renal cell carcinomas

T cell-replacing factor- (TRF) induced IgG secretion in a human B blastoid cell line and demonstration of acceptors for TRF.

B cell growth and differentiation factors and mechanism of B cell activation.

Effect of B cell differentiation factor (BCDF) on biosynthesis and secretion of immunoglobulin molecules in human B cell lines.

Functional and possible physical association of scavenger receptor with cytoplasmic tyrosine kinase Lyn in monocytic THP-1-derived macrophages