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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 655-658, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.F253

Perspective

15-Lipoxygenase

A Janus Enzyme?

Pascal Chanez, Caroline Bonnans, Claude Chavis and Isabelle Vachier

Clinique des Maladies Respiratoires, INSERM U454-IFR 3, CHU-Montpellier, France

Address correspondence to: Dr. Chanez Pascal, Clinique des Maladies Respiratoires, Hôpital Arnaud de Villeneuve, 371 Av du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France. E-mail: chanez{at}montp.inserm.fr

Abbreviations: interleukin, IL • lipoxygenase, LO • lipoxin A4, LXA4 • polymorphonuclear leukocyte, PMN


   Introduction
Top
 Introduction
Evidence for Two Different...
 15-Lipoxygenase and the Lung
 Biological Effects of 15-LO...
 Dual Function for 15-LO
 References
 
Bronchial diseases such as asthma and chronic obstructive pulmonary disease represent heterogenous clinical entities. Their symptoms are made of cough, chest tightness, shortness of breath, and mucus production, which contribute to airflow obstruction and bronchial hyperresponsiveness. Many bronchial and inflammatory cells contribute to these features. Their mediators are numerous and responsible for the perpetuation of the phenomena leading to the chronicity of the diseases. Research efforts to improve understanding are urgently needed because little is known of their natural histories, with particular interest in the loss of respiratory function. Current pharmacologic strategies help some, but not all, patients, and new avenues of treatment are worth investigating. Considering this important challenge, the arachidonic acid metabolism represents an important source of mediators with ambivalent actions. The present perspective will consider the case of the 15-lipoxygenase enzyme family, a well-known promoter of the emergence of proinflammatory mediators, when recently it was shown that some mediators with potential anti-inflammatory effects might emerge from their actions.


   Evidence for Two Different 15-Lipoxygenases
Top
 Introduction
 Evidence for Two Different...
15-Lipoxygenase and the Lung
 Biological Effects of 15-LO...
 Dual Function for 15-LO
 References
 
Lipoxygenases (LO) are a class of nonheme iron dioxygenases that catalyze the hydroperoxydation of polyunsaturated fatty acids containing pentadiene-cis systems. They are characterized by their ubiquity; they are present in seeds, vegetables, microorganisms, and animals. Pairwise sequence identity is 21–27% between plant and mammalian LO, but 43–86% between pairs of plant sequences and 39–93% between pairs of mammalian sequences. The highest sequence identity between these LO is in the portion of the catalytic domain near the iron atom (1). Among the members of this lipoxygenase family, 15-lipoxygenase (15-LO) is the lipid-peroxidizing enzyme which catalyses the insertion of molecular oxygen on arachidonic acid skeleton at carbon 15 position to produce 15(S)-HPETE, or on linoleic acid at 13 position to produce 13(S)-HPODE. Unlike the other LO, 15-LO is able to oxygenate esterified polyenoic fatty acids, constitutive of biologic membranes, without prior action of a phospholipase A2, and to be activated upon cell damage (2). Two different human 15-LO, named 15-LOa (initially named 12/15-LO and then 15-LO1) and 15-LOb (also named 15-LO2), have been identified by their differences in tissue distribution and substrate. 15-LOa was first purified in rabbit reticulocyte (3), and is highly expressed in human eosinophils (4) and human bronchial epithelial cells (5). 15-LOb has been described more recently by Brash and coworkers from hair roots and is expressed in prostate, skin, lung, and cornea (6). In contrast to the distribution of 15-LOa, 15-LOb was not detected in peripheral blood leukocytes, in liver, kidney, spleen, thymus, testis, ovary, skeletal muscle, heart, brain, or intestine (6). Nevertheless, cell treatment by interleukin (IL)-4 or IL-13 leads to 15-LOa induction in monocytes or carcinoma cell lines (7–11), without any effect on 15-LOb (12).

In terms of enzymatic activities, 15-LOa preferentially metabolizes linoleic acid into 13(S)-HODE and also metabolizes arachidonic acid into 15(S)-HETE. Moreover, 15-LOa produces small amounts of 12(S)-HETE in a ratio of 12/1 [15(S)-HETE/12(S)-HETE] (13). By contrast, 15-LOb converts arachidonic acid into 15(S)-HETE with a poor metabolization of linoleic acid. Moreover, 15-LO is able to produce lipoxins generated from LTA4 released by surrounding cells such as alveolar macrophages and leukocytes (14–16).

15-LOa and 15-LOb present only 31.6% homology at the amino acid level. Moreover, 15-LOa demonstrates a closer homology to 12-LO (65.1%). A novel splice variant of 15-LOb (15-LOb2) has been cloned from human prostate cDNA containing an in-frame 87-bp deletion (17). Different patterns of cellular expression of 15-LOa and b may suggest distinct biologic roles. They are both expressed in lung epithelial cells, suggesting possible additive or antagonistic effects in these cells.


   15-Lipoxygenase and the Lung
Top
 Introduction
 Evidence for Two Different...
 15-Lipoxygenase and the Lung
Biological Effects of 15-LO...
 Dual Function for 15-LO
 References
 
Holtzman and colleagues have shown that human tracheal epithelial cells presented markedly higher levels of 15-LO activity than other cell types (18). A number of studies in the 1990s reported 15-LO expression in human bronchial epithelial cells (4, 19–21). 15-LO is predominantly present at the epithelium level, and less was found in the rest of the lung (22). This was confirmed by Kumlin and coworkers, who showed a decrease of 15(S)-HETE release by removing the epithelial layer from bronchial fragments (23).

Several cells involved in lung inflammation also express 15-LO. Human eosinophils produce higher levels of 15(S)-HETE than neutrophils (4, 24). In contrast to blood monocytes, macrophages express 15-LO and release 15(S)-HETE (25).


   Biological Effects of 15-LO Products
Top
 Introduction
 Evidence for Two Different...
 15-Lipoxygenase and the Lung
 Biological Effects of 15-LO...
Dual Function for 15-LO
 References
 
15(S)-HETE and lipoxins may have paradoxical pro- and anti-inflammatory effects. Concerning 15(S)-HETE, two studies have investigated the effect of inhaled 15(S)-HETE in subjects with asthma and in control subjects. In the first study, inhaled 15(S)-HETE increased the early bronchoconstrictor response to inhaled allergen in patients with atopic asthma without affecting the late asthmatic response or the nonspecific bronchial responsiveness (26). This study indicated that 15(S)-HETE could affect the responses of mast cells, enhancing their leukotriene production. The second study showed that inhalation of 15(S)-HETE reduced airway responsiveness to methacholine and histamine without affecting baseline airway caliber (27).

Several ex vivo studies have demonstrated that 15(S)-HETE could have anti-inflammatory properties. 15(S)-HETE inhibits the activity of 5-LO, inhibiting leukotriene production by neutrophils (28–32). IL-4–induced expression of 15-LO in monocytes caused a significant reduction in LTB4 production (33). 15(S)-HETE inhibits LTB4-induced chemotaxis of human neutrophils (34) and superoxide anion generation (35). 15(S)-HETE inhibits neutrophil migration across cytokine-activated endothelium (36). The transfection of rat kidney with 15-lipoxygenase suppresses inflammation (37). Finally, using a murine model of airway inflammation, it was recently reported that the lungs of 12/15-LO deficient mice had more pronounced inflammatory responses than those of control mice (38).

Several lines of evidence suggest that lipoxins are mediators with putative anti-inflammatory properties. Inhaled lipoxin A4 (LXA4, 5S,6R,15S-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid) antagonizes the bronchoconstriction induced by leukotriene C4 (39). It has been shown that LXA4 has nonphlogistic actions on monocytes at nanomolar concentrations. LXA4 stimulates phagocytosis of apoptotic polymorphonuclear leukocytes (PMNs) by macrophages to resolve inflammation (40). LXA4 and LXB4 inhibit leukotriene and fMLP-induced neutrophil chemotaxis in vitro (41). LXA4 inhibits transmigration of PMNs across epithelial cells (42) and endothelial monolayers (43). In a recent study, we have shown that LXA4 decrease LTB4 released by human PMNs (32), and that exogenous LXA4 inhibited IL-8 released by peripheral blood mononuclear cells from individuals with severe and mild asthma (44). Moreover, in a murine model of asthma, LXA4 stable analogs blocked both airway hyperresponsiveness and pulmonary inflammation (45).


   Dual Function for 15-LO
Top
 Introduction
 Evidence for Two Different...
 15-Lipoxygenase and the Lung
 Biological Effects of 15-LO...
 Dual Function for 15-LO
References
 
Shannon and colleagues have shown by immunohistochemistry that 15-LO protein expression was increased in bronchial epithelial cells from subjects with asthma and subjects with chronic bronchitis (46). Concerning 15(S)-HETE, human epithelial cells obtained from patients with asthma released significantly more 15(S)-HETE as compared with control subjects (23, 47–49). Levels of both soluble and cell-associated 15(S)-HETE in the supernatant of induced sputum samples were higher in patients with asthma and those with chronic bronchitis than in control subjects (50, 51). 15(S)-HETE is increased following an allergen challenge of human airways from atopic subjects in vitro (52) and in vivo (53). In an animal model of asthma, it has been shown that 15(S)-HETE was increased in the lung (54).

LXA4 has been recovered in bronchoalveolar lavages of patients with respiratory diseases (25, 55) and in supernatants of induced sputum from patients with asthma (44). In this last study, we demonstrated that subjects with mild asthma present higher levels of LXA4 in supernatant of induced sputum as compared with subjects with severe asthma.

These results suggested that 15(S)-HETE and LXA4 are released in higher levels in patients with mild asthma. Patients with severe asthma present a deficit in LXA4 biosynthesis, but little is known about the generation of 15(S)-HETE in this situation.

This result was supported by Chu and coworkers, who showed that in endobronchial tissues, 15-LOb levels were higher in subjects with mild asthma than in those with severe asthma. By contrast, the 15-LOa/15-LOb ratio was higher in subjects with severe asthma as compared with those with mild asthma and control subjects (56). Taken together, these results allowed us to speculate that anti-inflammatory effects of lipoxins are related to the activity of 15-LOb when 15-LOa is increased in airway diseases. Moreover, 15-LOa and 15-LOb have opposite effects on epithelial cell proliferation/differentiation: the 15-LOb pathway could be antiproliferative, and the high 15-LOa/15-LOb ratio in individuals with severe asthma suggests a possible ongoing proliferative epithelial repair process (56), as recently reported on endobronchial tissue obtained from patients with severe asthma (57).

In the current issue of the AJRCMB, Zhu and coworkers bring new data supporting a role for 15-LO in airway diseases (58). They demonstrate that there is an upregulation of 15-LOa mRNA and protein expression in airway mucosa of smokers with or without chronic bronchitis as compared with the expression observed in lung tissue from healthy nonsmokers. 15-LOb expression was not differently expressed in biopsies from all subjects. The number of IL-4–positive cells was correlated with the number of 15-LOa and not with 15-LOb, suggesting a role for 15-LOa in chronic bronchitis, and perhaps associated with IL-4–driven inflammation and mucus hypersecretion. Further studies to elucidate the effect of 15(S)-HETE on mucus production and the relation between IL-4 and 15(S)-HETE release in these patients would be needed. Indeed, the effects of 15(S)-HETE on mucus release reported in literature are unclear at present. Initially, it was reported that 15(S)-HETE increased mucus secretion from human bronchial explants (59). But, more recently, it was reported that 15(S)-HETE precursor had no effect on mucin secretion and expression in normal human tracheobronchial epithelial cells (60), and that 15-LOa products did not mediate the IL-4–induced reduction of mucin secretion observed in human bronchial epithelial cells (12).

The duality in 15-LO function has been observed in other diseases such as cancer. Conrad and colleagues showed that in vivo 15-LOa have antitumor effects in human airway carcinomas, and that 15-LOa promote apoptotic pathway. They showed that neoplastic tissues from human airway carcinomas demonstrated nonspecific staining for human 15-LOa as compared with normal tissues (61). By contrast, in human prostate tumors 15-LOa was overexpressed as compared with normal adjacent tissue (62), and 15-LOb was poorly expressed in prostate tumors (63). In PC3 cells, 13(S)-HODE, one of the 15-LOa metabolites, upregulated MAP kinase, whereas in contrast 15(S)-HETE, the 15-LOb metabolite, downregulated MAP kinase (64).

Taken together, these findings including the upregulation of 15-LOa within the airway tissue of smoking patients with chronic bronchitis, provide new evidence of possible acquired abnormalities linked to airway inflammation. The bronchial epithelium is clearly a key player in inflammation and structural changes in airway diseases. Its rich content in 15-LOa– and 15-LOb–derived products highlight their potential as new target for therapeutic interventions (Figure 1). The development of synthetic analogs derived from 15-LO with potential anti-inflammatory properties might enlarge our armatorium to struggle with these airway diseases.



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  		Figure 1. Duality in 15-LO function in airway diseases.

 
Received in original form October 22, 2002


   References
Top
 Introduction
 Evidence for Two Different...
 15-Lipoxygenase and the Lung
 Biological Effects of 15-LO...
 Dual Function for 15-LO
 References
 

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