On the expression and regulation of 5-lipoxygenase in human lymphocytes.

Jakobsson, Per‐Johan; Steinhilber, Dieter; Odlander, Björn; Rådmark, Olof; Claesson, Hans‐Erik; Samuelsson, Bengt

doi:10.1073/pnas.89.8.3521

Cited by 98 publications

(100 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Differentiation in the presence of TGFP and 1,25-dihydroxyvitamin D, is essential for induction of high cellular 5-lipoxygenase activity in these cells. Moreover, B-lymphocytes and B-lymphocytic cell lines like BL41 -E95-A express 5-lipoxygenase protein and activity in cell homogenates, but intact cells do not release leukotrienes after stimulation with ionophore A23187 and arachidonic acid [22]. As shown in Table 1, suppression of cellular 5-lipoxygenase activity Me,SO-differentiated HL-60 and BL41-E95-A cells requires the presence of serum.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to mature monocytes or granulocytes, lymphocytes do not respond with leukotriene synthesis after stimulation with ionophore and arachidonic acid [22]. Therefore, it was interesting to check whether the inhibition of cellular 5-lipoxygenase activity in B-lymphocytes is due to selenium-dependent GSH-peroxidases or to selenium-independent peroxidase activity provided by GSH S-transferases.…”

Section: Characterization Of the Selenium-dependent Peroxidasementioning

confidence: 99%

“…Thus, agents that are able to increase cellular peroxide levels stimulate 5-lipoxygenase activity by providing a threshold peroxide level required for lipoxygenase reaction [21]. Also, after exposure to diamide or l-chloro-2,4-dinitrobenzene, B-lymphocytes become responsive to arachidonic acid plus ionophore as second stimulus [22]. In intact cells, peroxide levels are considered to be under the control of peroxidases [23].…”

mentioning

confidence: 99%

See 2 more Smart Citations

Selenium‐Dependent Peroxidases Suppress 5‐Lipoxygenase Activity in B‐Lymphocytes and Immature Myeloid Cells

Werz

Steinhilber

1996

European Journal of Biochemistry

View full text Add to dashboard Cite

Differentiation of HL-60 cells by dimethylsulfoxide induces 5-lipoxygenase protein expression, but only low cellular 5-lipoxygenase activity. Similarly, B-lymphocytes express 5-lipoxygenase protein and show activity in cell homogenates but not in intact cells. Here, we demonstrate that suppression of cellular 5-lipoxygenase activity in these cell lines is serum dependent and that the serum effect can be mimicked by selenium. Selenium-dependent inhibition of 5-lipoxygenase activity was also observed in the corresponding cell homogenates or 100 OOOXg supernatants when dithiothreitol or glutathione (GSH) was added. The properties of the endogenous selenium-dependent inhibitor, i.e. molecular mass, utilization of GSH and dithiothreitol as substrates, sensitivity to iodacetate, inhibition of 5-lipoxygenase activity in the presence of the GPx-1 inhibitor mercaptosuccinate, suggest that a selenoenzyme with properties of the phospholipid hydroperoxide glutathione peroxidase (GPx-4) is responsible for the 5-lipoxygenase inhibition in BL41-E95-A and immature HL-60 cells.Differentiation of HL-60 cells in the presence of 1,25-dihydroxyvitamin D, and transforming growth factor# (TGFP) upregulated cellular 5-lipox ygenase activity regardless of whether the cells were grown with or without serum or selenium. Also, 5-lipoxygenase activity in homogenates or lOOOOOXg supernatants of l ,25-dihydroxyvitamin DJTGFP differentiated HL-60 cells and of human granulocytes was not inhibited by dithiothreitol or GSH. Thus, after 1,25-dihydroxyvitamin DJTGFP differentiation, HL-60 cells resemble normal granulocytes with respect to the high 5-lipoxygenase activity in intact cells and to the dithiothreitol effects in broken cell preparations. Combination experiments with 100 OOOXg supernatants of BL41-E95-A cells and neutrophils revealed that the high 5-lipoxygenase activity of granulocytes is due to stability of the 5-lipoxygenase catalytic activity against selenium-dependent peroxidases, but not to low peroxidase activity. Our data suggest that the capability of mature myeloid cells to release large amounts of leukotrienes after stimulation is due to a peroxidase-insensitive 5-lipoxygenase catalytic activity.Keywords: 5-lipoxygenase; glutathione peroxidase; HL-60; cell differentiation; lymphocyte.Leukotrienes are mediators of inflammatory responses that can be formed in granulocytes, monocyteslmacrophages and mast cells after stimulation. 5-lipoxygenase catalyzes the first two steps of leukotriene biosynthesis from arachidonic acid [ l , 21. In neutrophils and HL-60 cells, 5-lipoxygenase is localized in the cytosol and translocates to the nuclear membrane after cell stimulation where it interacts with 5-lipoxygenase-activating protein [3-71. Recently, it has been shown that 5-lipoxygenase can associate with other proteins via interactions with SH3 domains and that tyrosine kinase activity has a prominent effect on cellular localization and activity of 5-lipoxygenase [8, 91. The capability of myeloid cells to release leukotrienes is upreg...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Characterization Of the Selenium-dependent Peroxidasementioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Selenium‐Dependent Peroxidases Suppress 5‐Lipoxygenase Activity in B‐Lymphocytes and Immature Myeloid Cells

Werz

Steinhilber

1996

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…PGs are synthesized de novo from membrane-released arachidonic acid when cells (including T cells) are activated by mechanical trauma or by specific cytokines, growth factors, and other stimuli (e.g., collagen and ADP in platelets, bradykinin, and thrombin in endothelium) (23,24). In this study, we link regulation of a newly identified pool of preformed CXCR3 and CXCR1 in human CD4 ϩ T cells with arachidonic acid and cyclooxygenase (COX) 3 activity.…”

mentioning

confidence: 99%

Cyclooxygenase Regulates Cell Surface Expression of CXCR3/1-Storing Granules in Human CD4+ T Cells

Gasser

Schmid

Zenhaeusern

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

Efficient migration of CD4+ T cells into sites of infection/inflammation is a prerequisite to protective immunity. Inappropriate recruitment, on the other hand, contributes to inflammatory pathologies. The chemokine/chemokine receptor system is thought to orchestrate T cell homing. In this study, we show that most circulating human CD4+ T cells store the inflammatory chemokine receptors CXCR3 and CXCR1 within a distinct intracellular compartment. Equipped with such storage granules, CD4+ T cells coexpressing both receptors increased from only 1% ex vivo to ∼30% within minutes of activation with PHA or exposure to the cyclooxygenase (COX) substrate arachidonic acid. Up-regulation was TCR independent and reduced by COX inhibitors at concentrations readily reached in vivo. The inducible inflammatory CXCR3highCXCR1+ phenotype identified nonpolarized cells, was preferentially triggered on CCR7+CD4+ T cells, and conferred increased chemotactic responsiveness. Thus, inducible CXCR3/1 expression occurs in a large fraction of CD4+ T cells. Its dependency on COX may explain a number of established, and point toward novel, effects of COX inhibitors.

show abstract

“…A possible explanation could be that a part of the 5-LO exists as dimer and/or in a complex with other soluble proteins. It is known that 5-LO in B-lymphocytes can be activated by treatment with diamide (Jakobsson et al , 1992 ). Thus, it is reasonable to assume that in the presence of high intracellular GSH levels, diamide leads to the glutathionylation of 5-LO.…”

Section: Discussionmentioning

confidence: 99%

Dimerization of human 5-lipoxygenase

Häfner¹,

Cernescu²,

Ermisch³

et al. 2011

Biological Chemistry

View full text Add to dashboard Cite

Human 5-lipoxygenase (5-LO) can form dimers as shown here via native gel electrophoresis, gel fi ltration chromatography and LILBID (laser induced liquid bead ion desorption) mass spectrometry. After glutathionylation of 5-LO by diamide/glutathione treatment, dimeric 5-LO was no longer detectable and 5-LO almost exclusively exists in the monomeric form which showed full catalytic activity. Incubation of 5-LO with diamide alone led to a disulfi debridged dimer and to oligomer formation which displays a strongly reduced catalytic activity. The bioinformatic analysis of the 5-LO surface for putative protein-protein interaction domains and molecular modeling of the dimer interface suggests a head to tail orientation of the dimer which also explains the localization of previously reported ATP binding sites. This interface domain was confi rmed by the observation that 5-LO dimer formation and inhibition of activity by diamide was largely prevented when four cysteines (C159S, C300S, C416S, C418S) in this domain were mutated to serines.

show abstract

On the expression and regulation of 5-lipoxygenase in human lymphocytes.

Cited by 98 publications

References 30 publications

Selenium‐Dependent Peroxidases Suppress 5‐Lipoxygenase Activity in B‐Lymphocytes and Immature Myeloid Cells

Selenium‐Dependent Peroxidases Suppress 5‐Lipoxygenase Activity in B‐Lymphocytes and Immature Myeloid Cells

Cyclooxygenase Regulates Cell Surface Expression of CXCR3/1-Storing Granules in Human CD4+ T Cells

Dimerization of human 5-lipoxygenase

Contact Info

Product

Resources

About