Decreased content of the IL1α processing enzyme calpain in murine bone marrow-derived macrophages after treatment with the benzene metabolite hydroquinone

Miller, Anita C.K.; Schattenberg, Diane G.; Malkinson, Alvin M.; Ross, David

doi:10.1016/0378-4274(94)90096-5

Cited by 35 publications

(22 citation statements)

References 25 publications

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“…The mouse macrophage cell line Raw264.7 was stably transfected with either pIL-1␣ or empty vector. Treatment of these cells with the calcium ionophore A23187 activates calcium sensitive calpain and results in the release of active IL-1␣ (5,19). As shown in Fig.…”

Section: Resultsmentioning

confidence: 92%

The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Werman

Werman-Venkert

White

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

336

283

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Although most cytokines are studied for biological effects after engagement of their specific cell surface membrane receptors, increasing evidence suggests that some function in the nucleus. In the present study, the precursor form of IL-1␣ was overexpressed in various cells and assessed for activity in the presence of saturating concentrations of IL-1 receptor antagonist to prevent receptor signaling. Initially diffusely present in the cytoplasm of resting cells, IL-1␣ translocated to the to nucleus after activation by endotoxin, a Toll-like receptor ligand. The IL-1␣ precursor, but not the C-terminal mature form, activated the transcriptional machinery in the GAL4 system by 90-fold; a 50-fold increase was observed using only the IL-1␣ propiece, suggesting that transcriptional activation was localized to the N terminus where the nuclear localization sequence resides. Under conditions of IL-1 receptor blockade, intracellular overexpression of the precursor and propiece forms of IL-1␣ were sufficient to activate NF-B and AP-1. Stable transfectants overproducing precursor IL-1␣ released the cytokines IL-8 and IL-6 but also exhibited a significantly lower threshold of activation to subpicomolar concentrations of tumor necrosis factor ␣ or IFN-␥. Thus, intracellular functions of IL-1␣ might play an unforeseen role in the genesis of inflammation. During disease-driven events, the cytosolic precursor moves to the nucleus, where it augments transcription of proinflammatory genes. Because this mechanism of action is not affected by extracellular inhibitors, reducing intracellular functions of IL-1␣ might prove beneficial in some inflammatory conditions.

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Section: Resultsmentioning

confidence: 92%

The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Werman

Werman-Venkert

White

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

336

283

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“…Lacking signal peptides, myristoylated cytokines, such as IL-1␣ and TNF-␣, are found as membrane-inserted proteins, where they are biologically active (43)(44)(45). Membrane IL-1␣ is cleaved by a calcium-activated calpain (46), and membrane TNF-␣ is cleaved by serine proteases, both resulting in the release of the cytokines into the extracellular space. In the present study, limited proteolysis of soluble recombinant IL-32␣ resulted in the formation of two peptides of 16 and 13 kDa.…”

Section: Discussionmentioning

confidence: 99%

Proteinase 3 is an IL-32 binding protein

Novick

Rubinstein

Azam

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

135

121

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IL-32, a recently discovered proinflammatory cytokine with four isoforms, induces IL-1␤, TNF-␣, IL-6, and chemokines. Here, we used ligand (IL-32␣) affinity chromatography in an attempt to isolate an IL-32␣ soluble receptor or binding protein. Recombinant IL-32␣ was covalently immobilized on agarose, and preparations of concentrated crude human urinary proteins were applied for chromatographic separation. A specific 30-kDa protein eluted from the column during acid washing and was identified by mass spectrometry as proteinase 3 (PR3) and confirmed by N-terminal microsequencing. PR3, a neutrophil granule serine protease, exists in a soluble or membrane form and is the major autoantigen for autoantibodies in the systemic vasculitic disease, Wegener's granulomatosis. The affinity of IL-32␣ to PR3 was determined by surface plasmon resonance. The dissociation constants were 2.65 ؎ 0.4 nM for urinary PR3 and 1.2 ؎ 0.05 nM for neutrophil-derived PR3. However, irreversible inactivation of PR3 enzymatic activity did not significantly change binding to the cytokine. Nevertheless, limited cleavage of IL-32 yielded products consistent with PR3 enzyme activity. Moreover, after limited cleavage by PR3, IL-32␣ was more active than intact IL-32␣ in inducing macrophage inflammatory protein-2 in mouse macrophages and IL-8 in human peripheral blood mononuclear cells. We suggest that PR3 is a specific IL-32␣ binding protein, independent of its enzymatic activity. However, limited cleavage of IL-32␣ by PR3 enhances activities of the cytokine. Therefore, specific inhibition of PR3 activity to process IL-32 or neutralization of IL-32 by inactive PR3 or its fragments may reduce the consequences of IL-32 in immune regulated diseases.autoimmune ͉ cytokine ͉ inflammation ͉ ligand affinity chromatography

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“…Along with the relatively new data about IL-1 suppression by benzene metabolites (19,(145)(146)(147)(148) (95,(195)(196)(197), which may be a rheumatoidlike (198) autoimmunity to IgG after chronic vinyl chloride exposure damages the IgG molecule. Other chemicals that induce autoimmune disturbances include halothane (184) and acetaldehyde (183), and biomarkers and symptoms in such disturbances exhibit variable data in multiple organs (197), indicating that several effects on the IRA may be occurring.…”

Section: Individual Ids Descriptionsmentioning

confidence: 99%

“…Gestational Zn deficiency appears to damage hippocampal and other functions (44,45,139,140). Chronic Zn deficiency reduces the IRA by deactivation of thymulin (133,(141)(142)(143)(144) (19,(145)(146)(147)(148) (158), including the brain (158), and it can cross the blood-brain barrier (159). Its effects include upregulation of IL-2, interferon, and other lymphokines; it acts as a chemoattractant for T and B cells, and it acts synergistically with IL-4 and IL-6.…”

Section: Individual Ids Descriptionsmentioning

confidence: 99%

Integrated Defense System Overlaps as a Disease Model: With Examples for Multiple Chemical Sensitivity

Rowat¹

1998

Environmental Health Perspectives

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Decreased content of the IL1α processing enzyme calpain in murine bone marrow-derived macrophages after treatment with the benzene metabolite hydroquinone

Cited by 35 publications

References 25 publications

The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Proteinase 3 is an IL-32 binding protein

Integrated Defense System Overlaps as a Disease Model: With Examples for Multiple Chemical Sensitivity

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