Role of lymphotoxin in expression of interleukin 6 in human fibroblasts. Stimulation and regulation.

Akashi, Makoto; Loussararian, A H; Adelman, Daniel C.; Saito, Minoru; Koeffler, H. Phillip

doi:10.1172/jci114401

Cited by 73 publications

(31 citation statements)

References 42 publications

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“…On the other hand, PKC has been implicated in the stabilization of a variety of other mRNAs such as, p21, GAP-43 and IL-1β itself [19,20,22,23]. Importantly, PKC has been convincingly implicated in COX-2 mRNA stabilization in several recent studies [21,31,44,54,68] and, indirectly, in IL-6 mRNA stabilization in one older study [69]. In astrocytes, PKC was previously shown to be important for IL-6 induction after IL-1β [70].…”

Section: Discussionmentioning

confidence: 98%

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a β-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-α and IL-1β. We found that IL-1β treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNAstabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1β is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications.

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Section: Discussionmentioning

confidence: 98%

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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“…The regulation of IL-6 expression at the molecular level is complex (67)(68)(69). PMA, as well as calcium ionophore and cAMP, was shown to up-regulate IL-6 gene expression in astrocytes (47,70,71), as well as to increase IL-6 mRNA stability (72), showing that PMA can regulate IL-6 secretion at multiple levels. Different PKC isoforms were shown to be involved in the regulation of IL-6 secretion (73)(74)(75)(76).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Interaction of Ingenol 3-Angelate with Protein Kinase C

et al. 2004

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Ingenol 3-angelate (I3A) is one of the active ingredients in Euphorbia peplus, which has been used in traditional medicine. Here, we report the initial characterization of I3A as a protein kinase C (PKC) ligand. I3A bound to PKC-␣ in the presence of phosphatidylserine with high affinity; however, under these assay conditions, little PKC isoform selectivity was observed. PKC isoforms did show different sensitivity and selectivity for down-regulation by I3A and phorbol 12-myristate 13-acetate (PMA) in WEHI-231, HOP-92, and Colo-205 cells. In all of the three cell types, I3A inhibited cell proliferation with somewhat lower potency than did PMA. In intact CHO-K1 cells, I3A was able to translocate different green fluorescent protein-tagged PKC isoforms, visualized by confocal microscopy, with equal or higher potency than PMA. PKC-␦ in particular showed a different pattern of translocation in response to I3A and PMA. I3A induced a higher level of secretion of the inflammatory cytokine interleukin 6 compared with PMA in the WEHI-231 cells and displayed a marked biphasic dose-response curve for the induction. I3A was unable to cause the same extent of association of the C1b domain of PKC-␦ with lipids, compared with PMA or the physiological regulator diacylglycerol, and was able to partially block the association induced by these agents, measured by surface plasmon resonance. The in vitro kinase activity of PKC-␣ induced by I3A was lower than that induced by PMA. The novel pattern of behavior of I3A makes it of great interest for further evaluation.

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“…Dermal fibroblasts also increase their level of IL-6 production when cultivated with T cells and this was even more pronounced with allogeneic cultures than when autologous T cells were used [115]. TNF-α, lymphotoxin (TNF-β) [110,116], IFN-γ [117], TGF-β1 [117] and IL-17A [117] represent T lymphocyte-produced cytokines that have been shown to Primary fibroblasts established from the lung tumor of a human cancer patient enhanced the production of IFN-γ by CD3/CD28 antibodyactivated autologous tumor-infiltrating lymphocytes over the level of IFN-γ produced by these T cells when they were activated without fibroblasts present upregulate fibroblast production of IL-6. IL-6 is important in the differentiation of naïve T lymphocytes into T H 17 cells that produce inflammatory IL-17A.…”

Section: Fibroblast Products As Promoters Of Inflammationmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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Role of lymphotoxin in expression of interleukin 6 in human fibroblasts. Stimulation and regulation.

Cited by 73 publications

References 42 publications

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Characterization of the Interaction of Ingenol 3-Angelate with Protein Kinase C

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

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