A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells

García-Verdugo, Ignacio; BenMohamed, Fatima; Tattermusch, Sonja; Leduc, Dominique; Charpigny, Gilles; Chignard, Michel; Ollero, Mario; Touqui, Lhousseine

doi:10.1183/09031936.00023111

Cited by 15 publications

(14 citation statements)

References 34 publications

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“…In humans, 12R-LOX has been detected in keratinocytes, tonsil squamous epithelial cells, bronchial epithelial cells, and psoriasis scales, as well as in B cells [8,70–74] . In mice, its expression has been induced at embryonic day (E) 15.5 in the epidermis, nasal epithelium, and surface of the tongue, suggesting that 12R-LOX is required for the proper development of neonates [71] .…”

Section: -Lipoxygenase 12r Type (12r-lox)mentioning

confidence: 99%

The role of lipoxygenases in pathophysiology; new insights and future perspectives

2015

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Lipoxygenases (LOXs) are dioxygenases that catalyze the formation of corresponding hydroperoxides from polyunsaturated fatty acids such as linoleic acid and arachidonic acid. LOX enzymes are expressed in immune, epithelial, and tumor cells that display a variety of physiological functions, including inflammation, skin disorder, and tumorigenesis. In the humans and mice, six LOX isoforms have been known. 15-LOX, a prototypical enzyme originally found in reticulocytes shares the similarity of amino acid sequence as well as the biochemical property to plant LOX enzymes. 15-LOX-2, which is expressed in epithelial cells and leukocytes, has different substrate specificity in the humans and mice, therefore, the role of them in mammals has not been established. 12-LOX is an isoform expressed in epithelial cells and myeloid cells including platelets. Many mutations in this isoform are found in epithelial cancers, suggesting a potential link between 12-LOX and tumorigenesis. 12R-LOX can be found in the epithelial cells of the skin. Defects in this gene result in ichthyosis, a cutaneous disorder characterized by pathophysiologically dried skin due to abnormal loss of water from its epithelial cell layer. Similarly, eLOX-3, which is also expressed in the skin epithelial cells acting downstream 12R-LOX, is another causative factor for ichthyosis. 5-LOX is a distinct isoform playing an important role in asthma and inflammation. This isoform causes the constriction of bronchioles in response to cysteinyl leukotrienes such as LTC4, thus leading to asthma. It also induces neutrophilic inflammation by its recruitment in response to LTB4. Importantly, 5-LOX activity is strictly regulated by 5-LOX activating protein (FLAP) though the distribution of 5-LOX in the nucleus. Currently, pharmacological drugs targeting FLAP are actively developing. This review summarized these functions of LOX enzymes under pathophysiological conditions in mammals.

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Section: -Lipoxygenase 12r Type (12r-lox)mentioning

confidence: 99%

The role of lipoxygenases in pathophysiology; new insights and future perspectives

2015

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“…to produce hydroperoxy products which further give rise to variety of lipid mediators performing important cellular functions [3]. Considerably enhanced activity of 12R-LOX enzyme is a common feature in psoriatic scales, proliferative dermatosis and pulmonary obstructive diseases suggesting its pivotal role in such pathology [ 13,14,15,16].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have attributed anti-inflammatory and wound healing properties to the extracts of this plant [25,26,27,28,29]. Enhanced activity of 12R-LOX has been hypothesized as the driving factor towards the inflammatory diseased conditions [14,16,33]. So it was very interesting to check if the anti-inflammatory property observed in Acalypha indica extracts is related to inhibition of 12R-Lipoxygenase enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…Pivotal role of 12R-LOX in skin physiology came into light with the discovery of high levels of 12R-HETE in psoriatic skin cells and also in various carcinoma cell lines [13,14,15]. Additionally, high 12R-LOX activity has also been involved in pathogenesis of pulmonary obstructive diseases where it has been established that 12R-LOX stimulates mucin production by ERK activation and sp1 translocation [16]. From the above studies it appears that a critical amount of 12R-LOX enzyme activity is essential for maintaining cell homeostasis and overexpression of the same leads to pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

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Cloning, expression, purification of active recombinant human 12R-LOX enzyme and its inhibition by Acalypha indica extracts

Fatima

Ramakrishna

Kumar

et al. 2017

Preprint

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12R-LOX over-expression has been reported in various pathologies such as psoriasis, proliferative dermatitis as well as pulmonary obstructive diseases indicating that this enzyme plays significant role in pathogenesis of inflammatory diseases. 12R-LOX, therefore, is a suitable target for therapeutic intervention with potential application of its inhibitors in the treatment of skin and other inflammatory disorders. Identification of such inhibitors requires sufficient quantity of active enzyme to be produced by an easy and cost effective expression systems and further development of a robust assay system to screen inhibitors against the 12R-LOX enzyme. Therefore, in the present study, a prokaryotic expression system was developed to over-express and purify active human 12R-LOX enzyme by a single step purification process. We have further standardized an HPLC based assay system to assess the activity of purified human 12R-LOX enzyme. We show here that purified 12R-LOX preferentially utilizes free arachidonic acid as the substrate but it is also active on methyl ester of arachidonic acid, albeit less efficiently. Additionally, using this assay system we observed the potent inhibition of human 12R-LOX enzyme activity by the ethyl acetate and aqueous sub-fractions of Acalypha indica leaves, which is widely used in traditional medicines for the treatment of various skin ailments PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2906v1 | CC BY 4.0 Open Access |

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“…Interestingly, inhibitors of the 12R-lipoxygenase have demonstrated an essential role in mucin expression. The inhibitors decreased MUC5AC mucin expression by the inhibition of the ERK/SP1 dependent mechanism (Garcia-Verdugo et al, 2012). LXA4 has been described as a significant signal for the inflammation resolution and is generated at a low level in the CF patients' lungs.…”

Section: Eicosanoids Pathwaymentioning

confidence: 99%

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

Mitri

Bardin

et al. 2020

Front. Pharmacol.

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Cystic fibrosis (CF) is the most common genetic disorder among Caucasians, estimated to affect more than 70,000 people in the world. Severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruction, are hallmarks of CF lung disease and participate in its progression. Anti-inflammatory therapies are, therefore, of particular interest for CF lung disease. Furthermore, a better understanding of the molecular mechanisms involved in airway infection and inflammation in CF has led to the development of new therapeutic approaches that are currently under evaluation by clinical trials. These new strategies dedicated to CF inflammation are designed to treat different dysregulated aspects such as oxidative stress, cytokine secretion, and the targeting of dysregulated pathways. In this review, we summarize the current understanding of the cellular and molecular mechanisms that contribute to abnormal lung inflammation in CF, as well as the new anti-inflammatory strategies proposed to CF patients by exploring novel molecular targets and novel drug approaches.

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A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells

Cited by 15 publications

References 34 publications

The role of lipoxygenases in pathophysiology; new insights and future perspectives

The role of lipoxygenases in pathophysiology; new insights and future perspectives

Cloning, expression, purification of active recombinant human 12R-LOX enzyme and its inhibition by Acalypha indica extracts

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

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