Malnutrition promotes prostaglandin over leukotriene production and dysregulates eicosanoid-cytokine crosstalk in activated resident macrophages☆
Introduction
In its synergy with infection, malnutrition contributes to 56% of all childhood deaths worldwide [1]. Previously, we have described a murine model of multinutrient undernutrition that mimics human weanling malnutrition [2]. In this model, we have shown that malnutrition leads to increased early dissemination of the intracellular parasite Leishmania donovani [2] and causes dysregulation of the macrophage pro-inflammatory cytokine network and nuclear factor kappa-B activation [3].
In addition to cytokines, lipid mediators such as eicosanoids (20-carbon molecules generated from arachidonic acid (AA)), also play an important role in inflammation. Two classes of eicosanoids important in the early inflammatory response are prostaglandins (PGs, a family of unsaturated polyoxygenated fatty acids) and leukotrienes (LTs, oxygenated fatty acids containing a conjugated triene). The initial step in prostaglandin production is the conversion of AA into PGG2 by cyclooxygenase. There are two distinct cyclooxygenase isoforms: COX-2 (induced by various inflammatory stimuli) and COX-1 (primarily constitutive; partially inducible). PGG2 is peroxidized to PGH2, which is then converted to various prostanoids, including PGE2 and PGI2 (prostacyclin), the two most abundant PGs in the murine system [4]. PGE2 and PGI2 share some biological activities because both increase intracellular levels of cyclic adenosine monophosphate (cAMP) [5], [6].
The first step in the biosynthesis of leukotrienes is the conversion of AA to LTA4 by 5-lipoxygenase (5-LO). Leukotriene A4 can be converted to LTB4 or conjugated with glutathione to yield LTC4. The latter is further converted to LTD4 and LTE4 by successive elimination of glutamyl and glycine residues. Leukotriene C4, LTD4, and LTE4, are collectively called cysteinyl leukotrienes (cysLTs). The LTs decrease levels of cAMP and increase levels of cyclic guanosine monophosphate (cGMP) [7], [8]. In general, the LTs are pro-inflammatory [9], whereas the PGs are anti-inflammatory [10].
Previously, we have shown in a murine model that malnutrition results in increased PGE2 release by cells from the local draining lymph node after cutaneous infection with L. donovani and that PGE2 levels correlate with the degree of parasite dissemination [2]. PGE2 has been implicated as an immunosuppressive mediator in other infections as well: cutaneous leishmaniasis [11], Mycobacterium avium infections [12], tuberculosis [13], leprosy [14], cysticercosis [15], influenza [16], and amebiasis [17]. Conversely, the LTs contribute to host defense in bacterial pneumonia [18], vesicular stomatitis virus encephalitis [19], histoplasmosis [20], schistosomiasis [21], Chagas’ disease [22], mycobacterial infections [23], cytomegalovirus infection [24], and toxoplasmosis [25].
Increased PGE2 production has been observed in various models of malnutrition [26], [27], [28], [29]. Skerrett reported that alveolar macrophages from protein and calorie-deficient rats had increased PGE2 and decreased LTB4 release after Listeria infection [28]. Lower levels of neutrophil LTC4 release have been reported in the malnourished elderly patients [30].
Both PGs and LTs are derived from AA and thus there may be a partition of the common substrate between these two enzymatic pathways. PGs and LTs counter-regulate each other and these two classes of eicosanoids have many opposing physiologic and cellular effects [31]. The limited previous work on eicosanoid regulation during malnutrition has not adequately addressed the relationship between these two classes of eicosanoids and the inter-relationship of these lipid mediators with the cytokine network. We hypothesized that malnutrition would produce an increase in immunosuppressive PGs relative to the pro-inflammatory LTs. To test this hypothesis, we studied the effect of multinutrient malnutrition on eicosanoid release from stimulated murine resident macrophages using two prototypical stimuli, lipopolysaccharide (LPS) and a calcium ionophore. In various macrophage systems, eicosanoid production is regulated by the IL-10, TNF-α, and GM-CSF [32], [33], [34], and therefore we investigated the relationship of eicosanoid levels to these cytokines in this model. Also, we investigated the hypothesis that inhibition of cyclooxygenase would decrease the abnormal level of PGs relative to the LTs.
Section snippets
Mice
Weanling (3-week old) female BALB/c mice were obtained from Charles River Laboratories, Inc. (Wilmington, MA). The experimental protocol was approved by the local institutional animal care and use committee.
Diets and feeding
Previously, we determined that the following feeding protocol mimics human weanling malnutrition [2]. Mice received a 3-d acclimation on standard chow after weaning and prior to the change to the two experimental diets. The control group (well-nourished (WN)) mice received a diet that
Results
LPS- or calcium ionophore-stimulated macrophages from malnourished mice produce increased levels of prostaglandins and decreased levels of leukotrienes.
Previously, we demonstrated that in a murine model that malnutrition results in increased PGE2 release by cells from the local draining lymph node after cutaneous infection with L. donovani, and that PGE2 levels correlate with the degree of early parasite dissemination [2]. These findings indicated that excessive PGE2 production in the
Discussion and conclusions
In a murine model of moderate human malnutrition, we investigated resident macrophage production of the two principal classes of lipid mediators involved in innate immunity, the prostaglandins (PGs) and leukotrienes (LTs). LTs (LTB4 and the cysteinyl leukotrienes LTC4, LTD4, and LTE4) are pro-inflammatory mediators, whereas PGs (PGE2 and PGI2) decrease the inflammatory response. This study examined these two classes of lipid mediators as a potentially integrated unit, because they both have a
Acknowledgements
The work was supported by funding from the US Department of Veterans Affairs (GMA, PCM), the San Antonio Area Foundation, and the University of Texas Health Science Center at San Antonio (Institutional Research Grant to GMA).
References (74)
- et al.
Regulation of macrophage-mediated tumor cell killing by prostaglandins; comparisons of the effects of PGE2 and PGI2
Prostaglandins
(1982) Actions of cytokines in relation to arachidonic acid metabolism and eicosanoid production
Prostaglandins Leukot. Essent. Fatty Acids
(1996)- et al.
Role of PGE2 on amoebic liver abscess formation in hamsters
Prostaglandins
(1997) - et al.
Leukotrienes play protective roles early during experimental VSV encephalitis
J. Neuroimmunol.
(2001) - et al.
Mice deficient for 5-lipoxygenase, but not leukocyte-type 12-lipoxygenase, displayed altered immune responses during infection with Schistosoma mansoni
Prostaglandins Other Lipid Mediators
(1998) - et al.
Role of leukotrienes in killing of Mycobacterium bovis by neutrophils
Prostaglandins Leukot. Essent. Fatty Acids
(2004) - et al.
Effects of inadequate vitamin E and/or selenium nutrition on the release of arachidonic acid metabolites in rat alveolar macrophages
Prostaglandins
(1989) - et al.
Malnutrition modifies pig small intestine inflammatory responses to rotavirus
J. Nutr.
(1999) - et al.
Granulocyte-macrophage colony-stimulating factor upregulates reduced 5-lipoxygenase metabolism in peripheral blood monocytes and neutrophils in acquired immunodeficiency syndrome
Blood
(1999) Arachidonate 5-lipoxygenase
Prostaglandins Other Lipid Mediators
(2002)
Prostaglandin E2 regulates inducible nitric oxide synthase in the murine macrophage cell line J774
Prostaglandins
Differential effects of inhibitors of cycloxygenase (cycloxygenase 1 and cyclooxygenase 2) in acute inflammation
Eur. J. Pharmacol.
Diverse coupling of cyclooxygenase 1 and 2 with final prostanoid synthesis in liver macrophages
Biochem. Pharmacol.
Effect of LTB4 on the inhibition of natural cytotoxic activity by PGE2
Cell. Immunol.
Factors affecting the cytokine production of human T cells stimulated by different modes of activation
J. Allergy Clin. Immunol.
Cysteinyl leukotrienes induce nuclear factor kappa B activation and RANTES production in a murine model of asthma
J. Allergy Clin. Immunol.
Release of arachidonic acid metabolites by human fetal membranes: interrelationship between leukotriene B4 and prostaglandin E2
Prostaglandins
The potentiating effects of malnutrition on child mortality; epidemiologic and policy implications
Nutr. Rev.
Malnutrition alters the innate immune response and increases early visceralization following Leishmania donovani infection
Infect. Immun.
Multinutrient malnutrition dysregulates the resident proinflammatory cytokine network, nuclear factor-κB activation, and nitric oxide production
J. Leukocyte Biol.
Physiological and pharmacological regulation of prostaglandin and leukotriene production by macrophages
J. Leukocyte Biol.
Prostaglandin E2 and I2 regulate intracellular adhesion molecule-1 expression in interleukin-1β-stimulated human gingival fibroblasts
J. Peridont. Res.
Negative inotropic effect of leukotrienes: leukotrienes C4 and D4 inhibit calcium-dependent contractile responses in potassium-depolarized guinea-pig myocardium
J. Pharmacol. Exp. Ther.
Thymocyte cyclic AMP and cyclic GMP response to treatment with metabolites issued from the lipoxygenase pathway
J. Immunol.
Leukotrienes: underappreciated mediators of innate immune responses
J. Immunol.
Indomethacin treatment slows disease progression and enhances Th1 response in susceptible BALB/c mice infected with Leishmania major
Parasite Immunol.
Chronic infection due to Mycobacterium intracellulare in mice; association with macrophage release of prostaglandin E2 and reversal by injection of indomethacin, muramyl dipeptide, or interferon-γ
J. Immunol.
The role of prostaglandin E2 in the immunopathogenesis of experimental pulmonary tuberculosis
Immunology
Induction of unresponsiveness to gamma interferon in macrophages infected with Mycobacterium leprae
Infect. Immun.
Taenia crassiceps cysticercosis: a role for prostaglandin E2 in susceptibility
Parasitol. Res.
Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus
Immunology
5-Lipoxygenase reaction products modulate alveolar macrophage phagocytosis of Klebsiella pneumoniae
Infect Immun.
Blockade of endogenous leukotrienes exacerbates pulmonary histoplasmosis
Infect. Immun.
Leukotriene B4 induces nitric oxide synthesis in Trypanosoma cruzi-infected murine macrophages and mediates resistance to infection
Infect. Immun.
Leukotriene B(4) protects latently infected mice against murine cytomegalovirus reactivation following allogeneic transplantation
J. Immunol.
LTB4 and LTC4 are absent in the cerebrospinal fluid of human immunodeficiency virus type 1-seropositive persons with toxoplasmic encephalitis: evidence for inhibition of 5-lipoxygenase by Toxoplasma gondii
J. Infect. Dis.
Immunosuppressive mechanisms in protein-calorie malnutrition
Surgery
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Sources of Support: Department of Veterans Affairs, San Antonio Area Foundation, University of Texas Health Science Center at San Antonio.