The encephalitogenic peptide pMOG 35-55 from the myelin oligodendrocyte glycoprotein was used to induce experimental autoimmune encephalomyelitis (EAE) in H-2b mice with the interleukin-6 (IL-6) gene intact or disrupted. The IL-6+/+ mice developed a chronic form of EAE ascending paralysis, whereas the IL-6-/- mice were resistant to the disease. Injections of recombinant IL-6 following pMOG immunization induced severe disease in the IL-6-/- mice. Histological examination of brain and spinal cord sections showed that the perivascular infiltration of inflammatory cells evident in IL-6+/+ mice was absent in the IL-6-/- animals and could be restored by exogenous IL-6 administration. Anti-MOG antibody levels were much lower in the IL-6-/- mice, but were not restored to high levels by IL-6 injections which elicited the development of pMOG 35-55-induced EAE. T lymphocytes reactive to the pMOG antigen were recovered from lymph nodes of both types of mice and Tcell lines could be established from both. Adoptive transfer of Tcell lines from IL-6+/+ mice induced EAE in the mice with the intact IL-6 gene but less in the IL-6-deficient mice, indicating that the resistant phenotype cannot be explained solely by lack of encephalitogenic Tcells. The absence of cell infiltrates in the brain and spinal cords of IL-6-/- mice upon adoptive transfer of the pathogenic Tcells from IL-6+/+ mice is consistent with a function of IL-6 in the local perivascular inflammatory process.
Interleukin-6 (IL-6) inhibits the growth of melanocytes and of early stage melanoma cells, but not that of advanced melanoma cells. The in vitro IL-6 response can be restored in the highly metastatic melamona B16-F10.9 by addition of recombinant soluble IL-6 receptor a-chain (sIL-6R). The F10.9 cells then undergo irreversible growth-arrest and show increased adherence with changes from epithelioid to spindleoid morphology. The sIL-6R is required for IL-6 to induce a sustained activation of the various Stat transcription factors which bind to speci®c IL-6 inducible enhancers. The sIL-6R and IL-6 combination causes an increase in the level of the anti-oncogenic transcription factor IRF-1 protein and DNA-binding, which remain elevated for 24 h. The promoter activity of the anti-oncogenic p21/Waf-1/Cip-1 gene is induced and accumulation of the p21 protein is observed. These results illustrate the potent agonist activity of sIL-6R on molecular pathways which could mediate the growth-arrest and di erentiation of the metastatic melanoma cells. Previously observed antimetastatic e ects of IL-6 therapy in mice bearing F10.9 tumors may be at least partly due to direct growth inhibition and di erentiation elicited by sIL-6R present in biological¯uids.
A number of studm have indicated that IL-6 exerts antitumoral activity in vim, in some leukemias and against metastasing tumors (see refs. 1 and 2 for reviews). These studies in murine models would support applications of IL-6 therapy in specific clinical settings, such as prevention of metastases following resections of primary tumors or prevention of relapses in certain types of leukemias. However, such clinical studies have not yet materidized, due to the limited understanding of how IL-6 works on various cells, why it stimulates growth of some cells (eg. myeloma and other hematopoietic cells) while inhibiting others, and due to the limited understandmg of the mechanisms underlying the antitumor effects observed. This article reviews what we have learned from studies on murine models of leukemias and metastases and from in vitro studies on a gene regulatory effect of IL-6 that may be relevant to growth control in many cell types.
EFFECTS OF IL-6 IN MURINE TUMOR MODELS
Myeloia Leukemia Mocl eXFThe recombinant human IL-6 glycoprotein produced in CHO-cells has been tested in radiation-induced acute myeloid leukemia (Rad-AML), either after intraperitoneal injection of tumor cells or during the primary induction period following irradiati~n.~ The latter model allowed to study 1L-6 action on bone marrow (BM) cells preceding the onset of overt leukemia. IL-6 was injected (1 pg/day/mouse, s.c.) for 10 days at 4-8 months after irradiation of SJLO mice (300-350 rads, plus dexamethasone). The incidence of leukemia and death at 1 year after irradiation was reduced from 50% in the controls to 20% in the IL-6-treated mice.3 Similar injections of GM-CSF increased, on the contrary, the leukemia incidence to 80%. A rapid disappearance of preleukemic cells present at 4 months in the BM of irradiated mice was observed 5 days after the end of the 10 days IL-6 treatment. These cells characterized by deletions
We investigated the anti-tumor effects of human recombinant interleukin-6 (hrIL-6) on the highly metastatic Lewis lung-carcinoma clone, D122. These cells express high-affinity IL-6 receptors at numbers comparable to the IL-6-dependent murine hybridoma B9 cells; however, IL-6 did not affect D122 cell proliferation or expression of MHC-class-I antigens in vitro. In vivo, treatment of mice bearing D122 tumors in the footpads, with a low dose of IL-6 in 3 daily injections, 4 days a week for 3 weeks, significantly decreased spontaneous metastases. However, only combined treatment of IL-6 and irradiated tumor cells resulted in almost complete protection against spontaneous metastases. Histological analysis confirmed the absence of micrometastases in most of the animals treated by this combination protocol. Analysis of the cytolytic activity of splenocytes at various time points during combined IL-6 and immunotherapy of tumor-bearing mice revealed significant and sustained lysis of the poorly immunogenic D122 carcinoma cells, while splenocytes of control mice could not lyse D122 target cells. Activation of specific immunity was also demonstrated when mice were pre-immunized with hrIL-6 and inactivated D122 cells and challenged with live carcinoma cells 10 days later. Significant growth inhibition of the primary tumor was observed.
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