Interleukin-4 Downregulates Interleukin-6 Production in Human Peripheral Blood Mononuclear Cells

Lee, Jeffrey D.; Swisher, Stephen G.; Minehart, E. H.; McBride, William H.; Economou, James S.

doi:10.1002/jlb.47.5.475

Cited by 54 publications

(21 citation statements)

References 17 publications

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“…TNF-␣ is known to induce IL-6 in endothelial cells, 38 fibroblasts, 39 neutrophils, 40 and mononuclear cells [41][42][43] ; our experiments indicate that the primary cell responsible for IL-6 mRNA expression in early reperfusion of the previously ischemic myocardium is the infiltrating mononuclear cell and suggest that TNF-␣ released from preformed stores in cardiac mast cells has a crucial role in inducing IL-6 in infiltrating mononuclear cells. As shown in Figure 13, several stimuli pertinent to ischemia may induce mast cell degranulation; it is possible that Ͼ1 of these stimuli are important.…”

Section: Hypothesized Cytokine Cascadementioning

confidence: 65%

Resident Cardiac Mast Cells Degranulate and Release Preformed TNF-α, Initiating the Cytokine Cascade in Experimental Canine Myocardial Ischemia/Reperfusion

et al. 1998

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Background-Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM-1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion. Methods and Results-Constitutive expression of TNF-␣ and not IL-1␤ was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-␣ in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-␣ in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-␣. Conclusions-Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-␣. We suggest that mast cell-derived TNF-␣ may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophilinduced injury. (Circulation. 1998;98:699-710.)

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Section: Hypothesized Cytokine Cascadementioning

confidence: 65%

Resident Cardiac Mast Cells Degranulate and Release Preformed TNF-α, Initiating the Cytokine Cascade in Experimental Canine Myocardial Ischemia/Reperfusion

et al. 1998

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“…On macrophages. it can inhibit the production of tumour necrosis factor (TNF), IL-I and lL-6 [17,18]. It is believed that IL-4 exerts its effects by interacting with cell surface receptors [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Expression of high-affinity IL-4 receptors on human melanoma, ovarian and breast carcinoma cells

Obiri¹,

Siegel²,

Varricchio

et al. 1994

Clinical and Experimental Immunology

107

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SUMMARY It has previously been shown that murine sarcoma cells express high‐affinity IL‐4 receptors (1L‐4R) which are internalized after binding to the ligand (Puri et al., Cancer Res 1991; 51:3011‐7). We have also reported that human renal cell carcinoma cells express high‐affinity IL‐4R. and IL‐4 inhibits tumour growth in vitro (Obiri et al, J Clin Invest 1993; 91:88). In this study we investigated the expression and function of IL‐4R on other human solid tumours. Human melanoma, ovarian carcinoma and breast carcinoma cell lines were assessed for the cell surface expression of IL‐4R by radio‐ligand receptor binding and for IL‐4R gene expression by Northern blot analysis. Primary cultures of mesothelioma and neurofibrosarcoma cells were similarly investigated. Human melanoma, ovarian carcinoma and breast carcinoma cell lines expressed IL‐4R on their cell surface with a dissociation constant (Kd) of 140‐549 pM. These tumour lines expressed a single 4 kb species of mRNA for IL‐4R. Similarly, primary cultures of mesothelioma and neurofibrosarcoma cells were positive for the IL‐4R mRNA by Northern blot analysis. Fresh, non‐cultured mesothelioma and neurofibrosarcoma tumour sections were also positive for the presence of IL‐4R as determined by immunohistochemistry of frozen sections using anti‐IL‐4R antibody. In order to study possible functions of IL‐4R, we evaluated the effects of 11.‐4 on cell growth and its effect on MHC antigen expression in the presence or absence of interferon‐gamma (IFN‐γ)‐ In tissue culture, IL‐4 reduced the growth of tumour cell lines and primary cell cultures studied. IL‐4 had very title effect on MHC class I antigen expression on ovarian, breast and melanoma cell lines; however. MHC class I (HLA‐DR) expression was enhanced on melanoma and breast carcinoma cells. IL‐4 also enhanced the IFN‐γ‐induced class II expression on melanoma and breast carcinoma cells. Taken together, our observations indicate that IL‐4R are expressed on a variety of human solid tumours and these receptors may be functional. IL‐4 alone and in combination with IFN‐γ may play a role in host immune response against cancers.

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“…IL-4, a product of T-helper cells, has been shown to upregulate IL-6 production in endothelial cells [5], in skin fibroblasts [6] and in keratinocytes [7], whereas it downregulates IL-6, IL-1 and TNFo! expression in human monocytes [8,9]. IL-13 is a novel T-helper cell lymphokine we have recently described [lO].…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐13 stimulates interleukin‐6 production by human keratinocytes

Derocq¹,

Ségui²,

Poinot-Chaze³

et al. 1994

FEBS Letters

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Interleukin-13 (IL-13) is a recently described human lymphokine which is produced by activated T-cells. Its effect on the production of IL-6 by normal keratinocytes and keratinocyte cell lines of human origin was studied and compared to that of IL-4. IL-13, similarly to IL-4, stimulated IL-6 expression by these cells in a dose-and time-dependent manner. Contamination with endotaxin was excluded by the use of polymyxin B and heat-inactivated cytokines. Further, we showed that IL-13, like IL-4, not only stimulated IL-6 production but also was able to induce overexpression of this cytokine in response to an inflammatory signal such as lipopolysaccharide (LPS). In a previous study, we demonstrated that IL-1 3, by inhibiting IL-6 and other cytokines produced by monocytes, exhibited an ~anti-in~ammato~ profile' comparable to that displayed by IL-4, In contrast, we show here that IL-B, by stimulating IL-4 production by keratinocytes, may favour the instaIlation of an ~~~ato~ process at a local level and, here again, it acted like IL-4. Therefore, according to the type of target cell, these two 'TH2 type' cytokines induce similar opposing effects on IL-6 production and are likely to be important cytokines in the regulation of inflation at bath systemic and 1ocaI levels.

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Interleukin-4 Downregulates Interleukin-6 Production in Human Peripheral Blood Mononuclear Cells

Cited by 54 publications

References 17 publications

Resident Cardiac Mast Cells Degranulate and Release Preformed TNF-α, Initiating the Cytokine Cascade in Experimental Canine Myocardial Ischemia/Reperfusion

Resident Cardiac Mast Cells Degranulate and Release Preformed TNF-α, Initiating the Cytokine Cascade in Experimental Canine Myocardial Ischemia/Reperfusion

Expression of high-affinity IL-4 receptors on human melanoma, ovarian and breast carcinoma cells

Interleukin‐13 stimulates interleukin‐6 production by human keratinocytes

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