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Interleukin-6 (IL-6) was produced by the spontaneously immortal Schwann cell clone, iSC, when cocultured with PC12 cells. The ISC cell-derived IL-6 in co-culture conditioned media caused the neuronal differentiation of naive PC12 cells and this bioactivity was neutralized by preincubation of conditioned media with antisera to IL-6. Cocultured ISC transcribe IL-6 message as confirmed by northern analysis. Stimuli that induce IL-6 production in the hematopoietic lineage induced transcription and production of IL-6 by ISC cells. Lipopolysaccharide, tumor necrosis factor-alpha, IL-1 alpha, IL-6, and serum withdrawal induced ISC cell IL-6 mRNA. The kinetics of IL-6 production was confirmed in the mouse IL-6-dependent B9 bioassay and that activity could be neutralized with antisera to IL-6. Expression of both the IL-6 receptor and the gp130 signal transduction component by iSC as determined by northern analysis suggests an autocrine regulatory mechanism. The observed iSC production of IL-6 in vitro led to an investigation of the sciatic nerve crush model of Schwann cell activation in vivo. In the initial 12 h after crush injury, IL-6 message is induced. IL-6 mRNA expression was highest distal to the crush injury. Our in vitro data demonstrate that iSC cells produce IL-6 in response to PC12 cell coculture and to stimuli that induce IL-6 production in the hematopoietic lineage. The induction of IL-6 message distal to a crush injury suggests another mechanism by which Schwann cells facilitate peripheral nerve regeneration.

In the present study, the requirements and characteristics for the production of IL-13 by human T cells, T cell clones and B cells were determined and compared with those of IL-4. IL-13 was produced by human CD4+ and CD8+ T lymphocyte subsets isolated from peripheral blood mononuclear cells and by CD4+ and CD8+ T cell clones. CD4+ T cell clones belonging to Th0, Th1-like and Th2-like subsets produced IL-13 following antigen-specific or polyclonal activation. In addition, EBV-transformed B cell lines expressed IL-13 mRNA and produced small amounts of IL-13 protein. Expression of IL-13 mRNA and production of IL-13 protein by peripheral blood T cells and T cell clones was induced rapidly and was relatively long lasting, whereas IL-4 production by these cells was transient. In addition, IL-13 mRNA expression was induced by modes of activation that failed to induce IL-4 mRNA expression. IL-13 shares many biological activities with IL-4 which is compatible with the notion that the IL-13 and IL-4 receptors share a common component required for signal transduction. However, IL-13 lacks the T cell-activating properties of IL-4. Here we have shown that this is related to the fact that T cells fail to bind radiolabeled IL-13 and do not express the IL-13-specific receptor component. Taken together, these results indicate that the differences in expression and biological activities of IL-4 and IL-13 on T cells may have consequences for the relative roles of these cytokines in the immune response.

Immunological ReviewsVolume 127, Issue 1 p. 5-24 Strategies of Anti-Cytokine Monoclonal Antibody Development: Immunoassay of IL-10 and IL-5 in Clinical Samples John S. Abrams, Corresponding Author John S. Abrams Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.John S. Abrams, DNAX Research Institute, 901 California Ave, Palo Alto, CA 94304, USA.Search for more papers by this authorMaria-Grazia Roncarolo, Maria-Grazia Roncarolo Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this authorHans Yssel, Hans Yssel Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this authorUlf Andersson, Ulf Andersson Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this authorGerald J. Gleich, Gerald J. Gleich Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this authorJon E. Silver, Jon E. Silver Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this author John S. Abrams, Corresponding Author John S. Abrams Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.John S. Abrams, DNAX Research Institute, 901 California Ave, Palo Alto, CA 94304, USA.Search for more papers by this authorMaria-Grazia Roncarolo, Maria-Grazia Roncarolo Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this authorHans Yssel, Hans Yssel Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this authorUlf Andersson, Ulf Andersson Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this authorGerald J. Gleich, Gerald J. Gleich Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this authorJon E. Silver, Jon E. Silver Departments of *Immunology and Human Immunology, DNAX Research institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304, USA; †Depart-ment of Immunology. Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden; and # Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, MN 55905. USA.Search for more papers by this author First published: June 1992 https://doi.org/10.1111/j.1600-065X.1992.tb01406.xCitations: 254AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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The syndrome of episodic angioedema and eosinophilia is characterized by cyclic edema, marked peripheral blood eosinophilia, and eosinophil degranulation in the dermis. Using a sensitive immunoenzymetric method, we measured serum interleukin (IL)-5 levels in four patients with this syndrome. We also determined the percentage of activated T cells in the peripheral blood of a new patient before and during an attack. In the patient presented, IL-5 levels peaked several days before maximal eosinophilia and then declined. This patient's lymphocytes showed an increased percentage, 28% (normal 2% to 3%), of activated T cells staining for both CD3 and HLA-DR 10 days before maximal eosinophilia, but no increase at the time of peak eosinophilia. In serum from three previously reported cases, elevated serum IL-5 levels were found during attacks. After glucocorticoid administration, IL-5 levels became undetectable in three of the four patients. Production of IL-5 is likely an important determinant of the pathophysiology of this syndrome.

Peripheral eosinophilia is almost invariably observed during the course of interleukin-2 (IL-2) therapy and is frequently accompanied by the development of a capillary leak syndrome characterized by edema, weight gain, and oliguria. We studied five patients with advanced malignancy treated with IL-2. Eosinophilia was not present initially but developed in all patients late in the course of therapy, with counts ranging from 2,328/mm3 to 15,958/mm3. In all patients, there was a temporal relationship between the infusion of IL-2 and the appearance of elevated plasma concentrations of IL-5, a growth factor for eosinophils. Granulocyte-macrophage colony-stimulating factor was not detectable in plasma. IL-4 and gamma-interferon plasma levels were variably elevated. Plasma concentrations of major basic protein, a toxic eosinophil granule protein, began increasing before eosinophil counts increased. By the time of the third IL-2 infusion, high concentrations of major basic protein were present in all five patients (up to 5,600 ng/mL) and skin biopsies showed major basic protein deposition in the dermis. Four patients developed significant capillary leak syndrome and all of these patients showed markedly elevated major basic protein levels. The lowest peak plasma concentration of major basic protein (1,751 ng/mL) was observed in the one patient who did not develop edema and weight gain. These results suggest that IL-2 induces IL-5 leading to marked peripheral eosinophilia and extravascular eosinophil degranulation. The release of toxic eosinophil products at extravascular sites and in the circulation may contribute to the pathogenesis of the capillary leak syndrome complicating IL-2 therapy.

To understand the role of the eosinophilopoietic cytokine IL-5 in humans, the posttreatment eosinophilic response in a group of microfilaria (mf)-positive patients with onchocerciasis (n = 10) was examined before and after treatment with diethylcarbamazine (6 mg/kg for 7 d). Sequential blood samples were assessed at 24 and 1 h before treatment (baseline values), then at frequent intervals over the next 14 d. Symptom scores, skin microfilariae (mf), and peripheral blood eosinophil counts were recorded as a function of time after treatment, and serum levels of IL-5 were quantitated by a highly sensitive (sensitivity greater than or equal to 20 pg/ml) monoclonal-based ELISA. Pretreatment eosinophil counts ranged from 240 to 1,186 eosinophils/microliter (geometric mean, 675), and the mf counts from 10 to 218 per mg skin (geometric mean, 79). After an initial decline in the peripheral eosinophil count to 28 +/- 8% of pretreatment levels at 8 h after beginning treatment, the eosinophil counts steadily increased over the next 2 wk, reaching a maximum at 14 d (257 +/- 38% of pretreatment levels). Serum levels of IL-5 rose sharply from pretreatment levels to a peak of 70.5 +/- 11 pg/ml by 24 h after treatment. Serum IL-5 remained elevated over the next 2-3 d and declined toward baseline by approximately 6 d after treatment, at which time the eosinophil levels were steadily increasing. IL-3 and granulocyte macrophage colony-stimulating factor, two other cytokines implicated in eosinophilopoeisis, were not detectable in the serum at any time before or after treatment. The rise in serum IL-5 before the posttreatment eosinophilia seen in this group of patients with onchocerciasis demonstrates a temporal relationship between IL-5 and the subsequent development of eosinophilia and implicates IL-5 as an important mediator of eosinophilia in humans.

Cytokine-induced differentiation of basophils may contribute to various inflammatory processes. We examined the effects of recombinant human interleukin-5 (IL-5) and other human cytokines in vitro on myeloid colony formation in methylcellulose and on alkaline passaged HL-60 basophilic cell differentiation. Myeloid colonies (CFU-C) at day 14, formed in the presence of either IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), or G-CSF included peripheral blood- derived progenitors of the eosinophil/basophil lineage. IL-5 stimulated a greater proportion of basophil-containing, histamine-positive, eosinophil-type colonies compared with GM-CSF, IL-3, or G-CSF. IL-5 also stimulated dose-dependent increases in histamine content of alkaline-passaged, butyrate cotreated HL-60 cells. The concentration of IL-5 required for half-maximal induction of HL-60 histamine content was similar within twofold to that needed for half-maximal stimulation of the multifactor dependent TF-1 erythroleukemic cell line. Neutralizing rat monoclonal antibodies to human IL-5 were developed and used to demonstrate that each of these IL-5 bioactivities could be specifically blocked. We conclude that in addition to its previously described eosinophil differentiation activity, IL-5 may be considered a basophilopoietin.