Anne Vink

Interleukin-9 and its receptor: involvement in mast cell differentiation and T cell oncogenesis.

Intcrleukin‐9 (IL‐9) is a multifunctional cytokine produced by activated TH2 clones in vitro and during TH2‐like T cell responses in vivo. The IL‐9 receptor is a member of the hemopoietin receptor superfamily and interacts with the γ chain of the IL‐2 receptor for signal transduction. Various observations indicate that IL‐9 is actively involved in mast cell responses by inducing the proliferation and differentiation of these cells. The role of IL‐9 in T cell responses is less clear. Although freshly isolated normal T cells do not respond to IL‐9, this cytokine induces the proliferation of murine T cell lymphomas in vitro and in vivo overexpression of IL‐9 results in the development of thymic lymphomas. In the human, the existence of an IL‐9‐mediated autocrine loop has been suggested for some malignancies such as Hodgkins disease. Other potential biological targets for IL‐9 include B lymphocytes, hematopoietic progenitors, and immature neuronal cell lines. J. Leukoc. Biol. 57: 353–360; 1995.

A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis

The p40 subunit of IL-12 (IL-12p40), but not the heterodimeric form IL-12p70, is secreted during the development of silica-induced lung fibrosis in C57BL/6 mice. To delineate the contribution of IL-12p40 to the lung inflammatory and fibrotic processes, we compared the pulmonary responses with silica particles of IL-12p35-deficient mice (IL-12p35−/−, able to produce IL-12p40) and IL-12p40-deficient mice (IL-12p40−/−). IL-12p35−/− and IL-12p40−/− animals developed strikingly contrasting responses to silica in comparison with wild-type C57BL/6 mice. Although the IL-12p40−/− mice exhibited limited inflammatory and fibrotic reactions, the IL-12p35−/− mice presented a robust and well-developed pulmonary inflammation and fibrosis. Furthermore, the silica-induced increase in lung IL-12p40 content was significantly higher in IL-12p35−/− mice than in wild-type controls, and was associated with extensive lung fibrosis and pulmonary macrophage infiltration. The contrasting responses observed between these two IL-12 subunit-deficient murine strains were not accompanied by a strict type 1 or type 2 polarization as estimated by the measurements of lung IFN-γ/IgG2a and IL-4/IgG1 content. In vitro proliferation, type I collagen expression, as well as myofibroblast differentiation of purified pulmonary fibroblasts were not affected by treatment with exogenous rIL-12p40. In vivo, supplementation with rIL-12p40 restored the impaired pulmonary fibrotic response and macrophage accumulation in silica-treated IL-12p40−/− mice, and also promoted fibrosis and macrophage influx in wild-type mice. Together, our data suggest that IL-12p40 plays an important role in silica-induced pulmonary inflammation and fibrosis, possibly by exacerbating macrophage recruitment.

Mouse Il-6 - a Hybridoma Growth-factor With Multiple Effects On Normal B-cells and T-cells

The effects of IL-6 on plasmacytomas and on normal B and T cells were examined. Evidence was presented to indicate that, in the mouse, IL-6 not only supports the growth of plasmacytomas in vitro, but also that it significantly enhances tumor progression in vivo. Analysis of the response of normal mouse B cells to IL-6 revealed the existence of a unique synergy between IL-6 and IL-1. The results obtained with T cells also highlighted the remarkable effects of the IL-1-IL-6 combination. In several experimental systems, including the generation of allogeneic cytolytic T cell responses, it appeared that accessory cells could be completely replaced by IL-1 and IL-6, whereas either cytokine used by itself was completely inactive. Analysis of the mode of action of IL-6 in T cell activation demonstrated the existence of two distinct mechanisms: induction of IL-2 biosynthesis and enhancement of T cell responsiveness to IL-2 and IL-4. Finally, it was reported that IL-6 is essential only during the early phases of T cell activation, thus indicating as far as T cells are concerned that IL-6 must be considered as a competence factor.

A monoclonal-antibody specific for the murine IL-6-receptor inhibits the growth of a mouse plasmacytoma in vivo

Antibodies specific for the human IL-6 receptor have been obtained by immunization with cells transfected with the cDNA for the 80kDa protein that was identified by Yamasaki as the human IL-6 receptor (Yamasaki, 1988; Hirata, 1989)). Unfortunately, similar reagents do not yet exist for the mouse IL-6 receptor.

B-cell and T-cell Responses Induced By Interleukin-6

Mouse interleukin-6 (DL6), formerly designated interleukin-HPl or PCT-GF, was originally identified as a growth factor for mouse plasmacytomas and hybridomas (Nordan and Potter 1986, Van Snick et al. 1986 and 1987). Natural mouse IL6 has been purified from supernatants of helper T cells (Van Snick et al. 1986), macrophages (Nordan et al. 1987) and fibroblasts (Cayphas et al. 1987), but it has also been found in high titers in the serum of lipopolysaccharide-treated mice (Coulie et al. 1987) and in supernatants of a wide range of tumor cells (unpublished observations).