Q J Med 2001; 94: 475-484
© 2001 Association of Physicians
The anti-inflammatory effects of circulating fatty acids in obstructive jaundice: similarities with pregnancy-induced immunosuppression
From the Medical Research Centre, 1 Department of Clinical Chemistry and 2 School of Human Development (University of Nottingham), Nottingham City Hospital NHS Trust, Nottingham, UK
Received 27 November 2000 and in revised form 12 June 2001
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionReferences |
|---|
Rheumatoid arthritis (RA) is ameliorated during both obstructive jaundice and pregnancy. Previous studies of polymorphonuclear leukocyte (PMN) function during pregnancy have shown reductions in the stimulated release of arachidonic acid (AA) and leukotriene B4 (LTB4), and lower NADPH oxidase activity. These changes may account for the amelioration of RA. The cause of this reduction in PMN function appears to be a progressive change in circulating fatty acids (FA), with a reduction in polyunsaturated FA, predominantly AA. The NADPH oxidase responsible for the respiratory burst has a direct requirement for polyunsaturated FA, particularly AA. We investigated whether the same changes in PMN function and FA, occur during obstructive jaundice. Patients with biliary obstructions were investigated before and after surgical correction (n=14). Obstructive jaundice caused significant changes in the proportions of serum and cellular FA. There was a striking reduction in polyunsaturated FA, particularly AA (48% in serum, p<0.001; 42% in PMNs, p<0.001) and an increase in mono-unsaturated oleic acid (24% in serum, p<0.001; 15% in PMNs, p<0.005). Similar changes occurred in mononuclear cell FA. Jaundice also caused a significant reduction in PMN function. Respiratory burst activity was reduced by between 32% and 38% in response to physiological and non-physiological stimuli, and there were similar significant reductions in the release of AA and LTB4. These changes in stimulated PMN function were evident whether or not the cells were first primed with tumour necrosis factor alpha (TNF
). Incubation of PMNs from healthy donors in pooled serum from patients with obstructive jaundice caused a reduction of 32% in cellular AA and 38% in NADPH oxidase activity. These findings support the idea that circulating FA can regulate PMN inflammatory responsiveness. The FA-induced attenuation in PMN activity in both jaundice and pregnancy may explain their ameliorating effects upon RA. |
Introduction |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
The activity of rheumatoid arthritis (RA) is significantly altered during pregnancy, with approximately 70% of patients experiencing substantial resolution of pain, swelling and stiffness.1 This improvement generally begins in the first trimester and progresses throughout gestation, but unfortunately relapses within 2 months of delivery.2 This effect of pregnancy has been noted for more than a century, but the first detailed account was published by Hench in 1938.3 In his description, Hench highlighted the observation that, ‘a very similar or identical phenomenon [to pregnancy-induced amelioration] is precipitated by jaundice in both male and female arthritic patients’. He also went further to suggest, ‘It does not seem illogical to suppose that the agents responsible for both these phenomena are closely related perhaps identical’.
Before this proposal, the work of Hench4 and others5–7 had already demonstrated that jaundice, like pregnancy, is associated with an improvement in joint symptoms. From these and further studies involving the ‘therapeutic’ induction of jaundice,8 disease remissions, although transient, were shown to be confined to hepatocellular and obstructive jaundice (but not haemolytic jaundice) and improvement was also evident in fibrositis and psoriatic arthritis9 in addition to RA. Similarities in the extent of these benefits, and the types of conditions affected, led Hench to his assertion that both jaundice and pregnancy may possess a single, common, anti-inflammatory denominator. From his clinical observations, Hench believed it particularly significant that women with remitting RA during pregnancy also noted benefits during periods of jaundice, while women whose arthritis did not improve, also remained unaffected when jaundiced.3
The mechanism(s) underlying the improvements in RA during pregnancy and jaundice is not understood. Certainly in pregnancy there is a general suppression of cell-mediated immunity,10 but this has not been established in jaundice. A reduction in stimulated polymorphonuclear leucocyte (PMN) function has been demonstrated in pregnancy, whereby chemotaxis,11 adherence12 and microbial killing13 are attenuated. Moreover, pregnancy serum has also been shown to influence PMN function by suppressing phagocytosis,14 bacterial killing15 and enzyme release.16 In our own studies, we have demonstrated a progressive decline in PMN NADPH oxidase activity, starting from the beginning of the second trimester, then progressing to term but recovering within 6 weeks of delivery.17 We have also demonstrated how similar changes occur in pregnant women with RA, and that these changes appear to coincide with the reported improvement in joint symptoms in responding RA patients.18
PMN are capable of causing unwanted tissue damage, and as such have been implicated in the inflammation and tissue destruction of RA.19 The PMN NADPH oxidase generates superoxide anions which are precursors of a variety of reactive oxygen molecules, many with destructive properties; in addition, eicosanoids, particularly leukotriene B4 (LTB4), are produced by PMN, and these can act as potent chemotoxins. In pregnancy, we have shown that altered NADPH oxidase activity is associated with a reduction in phospholipase A2 (PLA2) response and consequently a reduction in eicosanoid production.20 Considering the enormous numbers of PMNs which travel through an inflamed RA joint everyday, these combined changes may well explain, or at least contribute to, the improvement followed by relapse of RA during and after gestation.
A possible explanation for changes in PMN function in pregnancy is an alteration in the proportions of circulating fatty acids (FA). During pregnancy, there is a progressive reduction in the proportions of circulating polyunsaturated FA, particularly arachidonic acid (AA) and an increase in monounsaturated FA, particularly oleic acid.20 These changes in serum FA are accompanied by the similar changes in the proportions of cellular FA in PMN. By manipulating FA content in vitro, it has been shown that PMN phagocytosis,21 cytotoxicity,22 eicosanoid production20,23 and NADPH oxidase activity20,24 can all be influenced by changes in membrane FA. Polyunsaturated FA, particularly AA, appear to have a direct effect on the assembly and activation of PMN NADPH oxidase.25 Consequently, changes in the proportions of FA during pregnancy, provide a plausible explanation for altered PMN function. If indeed this is a mechanism underlying improvement in RA during pregnancy, then Hench's suggestion that an identical process occurs in jaundice can be tested.
Although in jaundice, macrophage phagocytosis26 and monokine production are reportedly reduced,27 little is known about PMN function. Prompted by Hench's observations, these investigations have monitored PMN function in patients with obstructive jaundice, both before and after surgical correction. In these experiments, NADPH oxidase activity, PLA2 activity and LTB4 production were measured in association with PMN fatty acid composition and circulating patterns of serum FA. Our aim was to investigate the hypothesis that serum FA are the common regulatory elements responsible for altered PMN function in pregnancy and thus the anti-inflammatory aspects of both pregnancy and jaundice.
|
Methods |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Patients
We studied 14 patients with extrahepatic cholestatic jaundice. All had large-duct biliary obstructions, which were subsequently corrected surgically. None had any condition known to influence fatty acid concentrations such as diabetes mellitus. Where administered, medication was restricted to antihistamines (chlorphenamine) and antibiotics (cefotaxime/metronidazole). A venous blood sample was drawn before surgery and a second sample was taken when bilirubin levels had returned to near normal (<30 µmol/l). By taking two samples, one before and one after treatment, each individual effectively acted as their own control. Table 1
shows the routine liver function tests for all these subjects. The possible effects of diurnal variation and cell activation on fatty acid values were avoided by taking blood in the morning with a large-bore needle. Informed consent was obtained in all cases and the study was approved by the Local Ethical Committee.
|
Reagents
Gentran 70 (6% dextran 70 in 0.9% NaCl) was supplied by Baxter Healthcare. EDTA (analytical grade) and BHT (2,6-di-ter-p-cresol) were BDH. Tritiated-AA ([3H]-AA) was from Amersham. Tumour necrosis factor alpha (TNF) was from Genzyme. All other reagents were from Sigma.
Preparation of PMNs and mixed mononuclear cells (MNCs)
Both human peripheral blood PMNs and MNCs were prepared by standard methods. Erythrocytes were sedimented on dextran, and the leucocyte-rich plasma was further purified by centrifugation over Histopaque 1077. After centrifugation, pelleted PMNs were retrieved, and MNCs were removed from a single band formed at the interface. Contaminating erythrocytes were lysed with 0.2% NaCl (w/v) and the osmolality was then restored with an equal volume of 1.6% NaCl (w/v). Once isolated, cells were washed twice in endotoxin-free phosphate-buffered saline (pH 7.2) (PBS) and their viability assessed by trypan blue exclusion. Both PMNs and MNCs were regularly obtained with a purity >96% and a viability >98%.
Fatty acid composition
Fatty acid analysis was performed on serum samples (200 µl) and aliquots of cell preparations (1–3x107 cells) by extraction of total lipids with methanol:benzene (4:1, v/v) plus BHT (0.5 mmol/l) as an antioxidant. FA were methylated by a direct transesterification technique,28 and the resulting fatty acid methyl esters were separated by gas-liquid chromatography, using a CPSil 88 50m capillary column (Chrompak) on a Hewlett-Packard 5890 Series II gas chromatograph.29 Peak identifications were made with commercially available reference FA. Fatty acid composition was expressed as relative molar percentages of fatty acid methyl esters, based on their peak areas.
Stimulation and priming
The agonists used were formyl peptide, n-formyl-Met-Leu-Phe (fMLP), complement C5a des arg in zymosan-activated serum (ZAS), and phorbol ester, 12,13-phorbol myristate acetate (PMA). A standard supply of ZAS was produced by the method of Fernandez et al.30 Sterile low endotoxin PBS was used as an unstimulated control. The priming agent was TNF (250 pg/ml). Cells were incubated for 30 min at 37 °C in the presence of TNF before stimulation.
Respiratory burst activity
Extracellular PMN superoxide anion production was measured by lucigenin-enhanced chemiluminescence (LUCL) using a Labsystems (Basingstoke, UK) Luminoskan plate-reading luminometer. Briefly, 140 µl PBS containing 1 mmol/l CaCl2, 0.7 mmol/l MgCl2 and 0.1% (w/v) endotoxin-free bovine serum albumin (PBS/Ca/Mg/BSA), 20 µl of 250 µmol/l lucigenin (bis-N-Methylacridinium Nitrate) and 20 µl PMN suspension (1x107/ml) were added to triplicate wells of a 96-well Immunofluor microtitre plate (Dynatech). The plates were warmed in the luminometer to 37 °C before the addition of either 20 µl fMLP (10 µmol/l), ZAS (50% v/v) or PMA (100 ng/ml). Chemiluminescence light output was monitored every 60 s for 30 min, and the integral over this period was expressed as relative light units (RLUs). The coefficient of variation for assay variability was 4.8%.
Measurement of phospholipase A2 (PLA2) activity
The general activity of PLA2 can be measured by labelling the phospholipid pool with tritiated arachidonic acid ([3H]-AA) and measuring its subsequent release following cell stimulation. PMNs at 1x107/ml were incubated with 1 µCi/ml [3H]-AA at 37 °C for 1 h in PBS/Ca/Mg/fatty-acid-free BSA. Cells were washed three times and resuspended in PBS/Ca/Mg/fatty-acid-free BSA at a concentration of 3x107/ml. Cell suspensions were either primed with TNF or left unprimed. Aliquots (100 µl) were stimulated with 1 µmol/l fMLP at 37 °C. The reactions were stopped at times 0 and 20 min by the addition of 0.5 ml ice-cold NaCl (0.9% w/v). PMNs were sedimented by centrifugation and the [3H]-AA in the supernatant and pellet measured by liquid scintillation counting. The coefficient of variation for assay variability was 5.2%.
Determination of leukotriene B4 (LTB4) generation
A commercially-available ELISA (R&D Systems) was used to determine the generation of LTB4. Cell suspensions of primed (TNF) or unprimed PMNs (1x107/ml) in PBS/Ca/Mg/BSA were pre-incubated at 37 °C for 10 min before the addition of fMLP (final concentration 1 µmol/l). The reaction was terminated by the addition of ice-cold citric acid (0.035 mol/l) to reduce the pH to 5.5. PMNs were sedimented by centrifugation, and the supernatants were removed and stored at -80 °C before being assayed. The coefficient of variation for the LTB4 ELISA was 3.6%.
Statistical analysis
Statistical significance of difference for normally distributed data was determined using a Student t-test for independent or paired samples (with or without a Bonferroni correction for multiple comparisons). Normal distribution was assessed by the Shapiro-Wilk significance level normality test. The results are presented as means and standard errors of the means (SEM) with the data considered significant at p<0.05 using two-sided significance.
|
Results |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Fatty acids in obstructive jaundice
Tables 2
, 3 and 4 show the major fatty acid constituents of serum, PMNs and MNCs, before and after correction of jaundice. In the case of serum FA, palmitic, oleic and linolenic acid were elevated, while stearic, linoleic, AA, eicosapentaenoic and docasahexaenoic acid were all significantly reduced. For isolated PMNs, a similar pattern of reductions and elevations in these FA was evident. In MNCs, palmitic, oleic and linoleic acid were again increased in jaundice, whereas stearic, AA, eicosapentaenoic and docasahexaenoic acid were all diminished. A general pattern of changes can be seen in Figure 1, showing an overall shift from polyunsaturated to monounsaturated FA during jaundice. We have previously reported a similar shift in serum and PMNs in the third trimester of pregnancy.20 These pregnancy values have been included for comparison and have been reproduced by permission (American Society for Microbiology). In these pregnancy studies, a significant reduction in stearic and AA and a significant increase in oleic and -linolenic acid were recorded (Table 5).
|
|
|
|
|
Respiratory burst activity in jaundice
Lucigenin is a cell-impermeable probe that amplifies photoemissions from oxygenation events. It is highly selective for the extracellular generation of superoxide anions, and thus provides a convenient measure of PMN NADPH oxidase activity. During jaundice, as compared with following treatment, PMN respiratory burst activity stimulated by fMLP, ZAS and PMA was reduced by 32% (p<0.05), 36% (p<0.05), and 38% (p<0.05), respectively (Figure 2). Unstimulated PMNs showed no significant differences in chemiluminescence output. These data indicate that superoxide anion production is considerably reduced during obstructive jaundice, and that this reduction applies to stimulation with physiological agonists, acting through cell surface receptors (fMLP and ZAS), as well as a stimulation that bypasses these receptor pathways (PMA). Overall, these figures are similar to those recorded previously in pregnancy.18 As with jaundice, there were no significant differences in chemiluminescence from unstimulated PMNs. However, PMNs from pregnant donors did show a reduction of 54% in response to fMLP, compared with non-pregnant controls, and 69% in response to ZAS.
|
PLA2 activity and LTB4 production in jaundice
PLA2 catalyses the hydrolysis of the ester bond of a fatty acid and the hydroxyl group at the sn-2 position of the glycerol backbone of a phospholipid to generate a lysophospholipid and a fatty acid (usually AA). Once AA has been liberated from membrane phospholipids, it can be further metabolized by PMN 5-lipoxygenase to yield LTB4, a potent inflammatory mediator, capable of both priming PMNs and activating the NADPH oxidase system. In these experiments, PLA2 activity and the potential for eicosanoid production were measured through the release of free AA and the liberation of LTB4. In response to fMLP, PLA2 activity was significantly reduced in PMNs from jaundiced subjects compared with those following treatment (Figure 3). Moreover, cells primed with TNF prior to activation also showed a marked reduction in their stimulated responses. No differences were evident in the resting cell responses in either the PLA2 or LTB4 assays. However, in the case of both primed (TNF) and unprimed conditions, cells from jaundiced patients did show a marked reduction in LTB4 production following fMLP stimulation (Figure 4). Once again, compared with relevant controls, a similar pattern of reduction in cell function has been demonstrated for jaundiced patients to those previously shown in third trimester pregnant women.20
|
|
Serum incubations
To further investigate the relationship between cellular and circulating fatty acid levels and PMN NADPH oxidase activity, PMNs isolated from healthy subjects were incubated (5 h, 37 °C) in either heat-inactivated (56 °C, 30 min) pooled serum from jaundice patients, or pooled serum from the same patients following treatment. Figure 5 shows that incubation in serum from jaundice patients modifies the cellular fatty acid profile of normal PMNs, bringing it into line with those already shown to be associated with jaundice. At the same time, the fMLP-stimulated respiratory burst of these cells is reduced to a level corresponding to that of jaundiced patients. Incubation of normal PMNs in serum from patients following correction of their jaundice had no significant effect, either on their fatty acid content or their respiratory burst activity.
|
|
Discussion |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Clinically, the beneficial effects of jaundice upon inflammatory arthritis appear to be strongly related to those of pregnancy. Certainly the types of disorders influenced, and the magnitude of these effects would suggest a possible link between these two conditions. Improvements in RA as a result of jaundice are highly reminiscent of those of pregnancy, especially those remissions seen in late gestation. With notable exceptions, these benefits are usually transient, with symptoms returning either soon after delivery in the case of pregnancy, or soon after liver functions have normalized in the case of jaundice. Following on from our previous observations in pregnancy, this study has investigated the possibility that changes in circulating FA may have both an indirect influence on oxygen radical production and a more direct effect on PMN inflammatory eicosanoid generation. Jaundice, as with pregnancy earlier, was thus investigated in terms of both fatty acid modifications and ex vivo PMN function.
During obstructive jaundice there are striking changes in the proportions of FA in serum, PMNs and MNCs (Tables 2
, 3 and 4). These changes, as in pregnancy (Table 5), are much larger than those possible by dietary intervention alone. These data are consistent with those of Scriven et al.31 who showed similar changes in FA content of phospholipids in the plasma and red cells of patients with obstructive jaundice.31 This appears to be the only previous report in the literature concerning FA in jaundice. Scriven et al. speculated that the cells of the reticuloendothelial system would be highly sensitive to changes in membrane fatty acid composition, and although they did not determine macrophage fatty acids, they suggested that a rise in fatty acid saturation might explain some of the jaundice-induced changes in these cells. We have now demonstrated such changes in MNC in jaundice.
Flesch et al.32 have shown that the incorporation of polyunsaturated fatty acids into macrophage phospholipids is accompanied by an increase in PLA2 activity and superoxide anion generation. A reduction in polyunsaturated fatty acids within PMN might therefore limit oxidase activity and reduce oxygen free-radical release. Our studies,20 with that of Bellavite et al.,33 have confirmed this relationship and have shown a convincing correlation between the amount of AA in PMN and their NADPH oxidase activity. The fact that incubation of normal cells in serum from jaundiced patients produces the same changes in cell FA and function, would strongly suggest that the one potentiates the other. Support for this also comes from our previous observations in pregnancy, which demonstrated reductions in PMN respiratory burst activity coupled with significant changes in cellular FA levels.20
There are at least two ways in which proportions of FA might influence inflammatory cell function. AA, released by the action of PLA2, is the precursor for LTB4, an extremely potent chemotactic agent. At high concentrations, LTB4 can stimulate the NADPH oxidase, as can AA. Thus, the reduction in polyunsaturated FA and increase in monounsaturated FA during obstructive jaundice and pregnancy could explain the observed reduction in release of AA and LTB4, as well as the reduction in NADPH oxidase activity. A second possibility is that the proportions of FA incorporated into phospholipids can influence cell function by a change in membrane fluidity. Although not addressed in this present study, or in our previous studies of pregnancy, this effect may nevertheless be inferred, as membrane fluidity is dependent on chain length and saturation of phospholipid FA. The shift from polyunsaturated to monounsaturated FA in both conditions will undoubtedly influence membrane fluidity, and will affect many cell functions, including that of the NADPH oxidase, a multi-component enzyme assembled in the membrane during PMN activation.
In the past, the beneficial effects of jaundice on RA were well known, so much so that rather bizarre attempts were made to induce jaundice in rheumatoid arthritic patients.8 Improvement in joint symptoms resulting from these treatment were short-lived, and like pregnancy, were considered to be more of a transient phenomenon than a prolonged event. This was one of the reasons for Hench's suggestion that the improvement in RA in these two quite different situations, might be due to closely related or identical agents. Previous attempts to identify these agents have concentrated on pregnancy and have ignored obstructive jaundice completely. The most popular candidates have therefore been hormones, particularly estrogen, progesterone and cortisol, and various pregnancy-associated proteins. Although some have shown regulatory effects upon lymphocyte function,10,33–35 none has satisfactorily explained the improvement and relapse in inflammatory arthritis. If pregnancy and obstructive jaundice share a common mechanism in improving RA, it follows that, as the beneficial effects of obstructive jaundice are shared equally between men and women, the influence of many of these factors can be ruled out. Undoubtedly there are many changes in both obstructive jaundice and pregnancy and it may be simplistic to attribute improvement to one factor alone. However, if looking for anti-inflammatory ‘agents’ that both pregnancy and obstructive jaundice have in common, then a possible candidate must include alterations in circulating FA.
Of the observed changes in FA in pregnancy and jaundice, the most important differences appear to be a reduction in polyunsaturated FA, particularly AA, and an increase in monounsaturated FA. It does not necessarily follow that these FA changes are due to the same mechanism in both conditions, but it is an intriguing prospect. The possibility that these effects are more widespread and may be influencing other cells of the immune system is presently under investigation. Although the down-regulation of PMN oxygen free radicals may be important in the amelioration of inflammation, it is unlikely, by itself, to explain the striking improvements in RA. Indeed, a much stronger association lies between disease progression and the activation of joint lymphocytes, macrophages, and the cytokines they produce. Recent evidence suggests that pregnancy-induced reversal of cytokines, from a pro-inflammatory Th1-type to an anti-inflammatory Th2-type response, might be instrumental in the relief of RA,36 and that dietary fatty acids in mice can influence the production of Th1-type cytokines.37 Given these observations, the influence of FA in the regulation of cytokines is now a focus of our continued research.
Although these results are inconclusive, we have shown that changes in the proportions of FA in pregnancy and jaundice have direct effects on PMN responsiveness. The extrapolation of these differences to improvements in inflammatory arthritis has yet to be established. However, the importance of FA in disease activity could be investigated by monitoring PMN activity in animal models of RA following induction of jaundice or pregnancy, or even during dietary manipulation.
|
Notes |
|---|
Address correspondence to Dr I.P. Crocker, Division of Obstetric and Gynaecology, University of Nottingham, Nottingham City Hospital NHS Trust, Hucknall Road, Nottingham NG5 1PB. e-mail: ian.crocker{at}nottingham.ac.uk
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
1. Spector TD, Da Silva JAP. Pregnancy and rheumatoid arthritis: an overview. Am J Reprod Immunol1992; 28:222–5.
2. Persellin RH. The effect of pregnancy on rheumatoid arthritis. Bull Rheum Dis1976; 27:922–7.[Medline]
3. Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis and intermittent hydrarthrosis. Proc Staff Meet Mayo Clinic1938; 13:161–7.
4. Hench PS. Analgesic accompanying hepatitis and jaundice in cases of chronic arthritis, fibrositis and sciatic pain. Mayo Clin Proc1933; 8:430–63.
5. Still GH. On a form of chronic joint disease in children. Trans Roy Soc Med Chir1897; 80:47–59.
6. Wishart J. A link between rheumatoid arthritis and jaundice. Br Med J1903; 1:252.
7. Sidel N, Abrams MI. Jaundice in arthritis: its analgesic action. N Engl J Med1934; 210:181–2.
8. Sullivan SN. The effect of jaundice on rheumatoid arthritis. J Rheumatol1980; 7:417–18.[Medline]
9. Hench PS. The advantage of hepatic injury and jaundice in certain conditions, notably the rheumatic diseases. Med Clin North Am1940; 24:1209–37.
10. Weinberg ED. Pregnancy-associated depression of cell-mediated immunity. Rev Infect Dis1984; 6:814–31.[ISI][Medline]
11. Krause PJ, Ingardia CJ, Pontius LT, Malech HL, LoBello TM, Maderazo EG. Host defense during pregnancy: neutrophil chemotaxis and adherence. Am J Obstet Gynecol1987; 157:274–80.[Medline]
12. Bjorksten B, Soderstrom T, Damber MG, von Schoultz B, Stigbrand T. Polymorphonuclear leucocyte function during pregnancy. Scand J Immunol1978; 8:257–62.[Medline]
13. El-Maallem H, Fletcher J. Impaired neutrophil function and myeloperoxidase deficiency in pregnancy. Br J Haematol1980; 44:375–81.[Medline]
14. Persellin RH, Thoi LL. Human polymorphonuclear leukocyte phagocytosis in pregnancy. Development of inhibition during gestation and recovery in the postpartum period. Am J Obstet Gynecol1979; 134:250–5.[Medline]
15. Persellin R H, Leibfarth JK. Studies of the effects of pregnancy serum on polymorphonuclear leukocyte functions. Arthritis Rheum1978; 21:316–25.[Medline]
16. Hempel KH, Fernandez LA, Persellin RH. Effect of pregnancy sera on isolated lysosomes. Nature1970; 225:955–6.[Medline]
17. Crouch SP, Crocker IP, Fletcher J. The effect of pregnancy on polymorphonuclear leukocyte function. J Immunol1995; 155:5436–43.[Abstract]
18.
Crocker IP, Baker PN, Fletcher J. Neutrophil function in pregnancy and rheumatoid arthritis. Ann Rheum Dis2000; 59:555–64.
19. Edwards SW, Hallett MB. Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunol Today1997; 18:320–4.[Medline]
20.
Crocker I, Lawson N, Daniels I, Baker P, Fletcher J. Significance of fatty acids in pregnancy-induced immunosuppression. Clin Diagn Lab Immunol1999; 6:587–93.
21. Schroit AJ, Gallily R. Macrophage fatty acid composition and phagocytosis: effect of unsaturation on cellular phagocytic activity. Immunology1979; 36:199–205.[Medline]
22. Schlager SI, Meltzer MS. Role of macrophage lipids in regulating tumoricidal activity. II. Internal genetic and external physiologic regulatory factors controlling macrophage tumor cytotoxicity also control characteristic lipid changes associated with tumoricidal cells. Cell Immunol1983; 80:10–19.[Medline]
23. Billiar TR, Bankey PE, Svingen BA, Curran RD, West MA, Holman RT, Simmons RL, Cerra FB. Fatty acid intake and Kupffer cell function: fish oil alters eicosanoid and monokine production to endotoxin stimulation. Surgery1988; 104:343–9.[ISI][Medline]
24. Corey SJ, Rosoff PM. Unsaturated fatty acids and lipoxygenase products regulate phagocytic NADPH oxidase activity by a nondetergent mechanism. J Lab Clin Med1991; 118:343–51.[ISI][Medline]
25. Dana R, Malech HL, Levy R. The requirement for phospholipase A2 for activation of the assembled NADPH oxidase in human neutrophils. Biochem J1994; 297:217–23.
26. Katz S, Grosfeld JL, Gross K, Plager DA, Ross D, Rosenthal RS, Hull M, Weber TR. Impaired bacterial clearance and trapping in obstructive jaundice. Ann Surg1984; 199:14–20.[Medline]
27. Jiang WG, Puntis MC. Immune dysfunction in patients with obstructive jaundice, mediators and implications for treatments. HPB Surg1997; 10:129–42.[Medline]
28. Lepage G, Roy CC. Direct transesterification of all classes of lipids in a one-step reaction. J Lipid Res1986; 27:114–20.[Abstract]
29. Taylor AJ, Pandov HI, Lawson N. Determination of erythrocyte fatty acids by capillary gas liquid chromatography. Ann Clin Biochem1987; 24:293–300.
30.
Fernandez HN, Henson PM, Otani A, Hugli TE. Chemotactic response to human C3a and C5a anaphylatoxins. I. Evaluation of C3a and C5a leukotaxis in vitro and under stimulated in vivo conditions. J Immunol1978; 120:109–15.
31.
Scriven MW, Horrobin DF, Puntis MC. Study of plasma and red cell phospholipid fatty acids in extrahepatic cholestatic jaundice. Gut1994; 35:987–90.
32. Flesch I, Ferber E. Effect of cellular fatty acid composition on the phospholipase A2 activity of bone marrow-derived macrophages and their ability to induce lucigenin-dependent chemiluminescence. Biochim Biophys Acta1986; 889:6–14.[Medline]
33. Bellavite P, Guarani P, Biasi D, Carletto A, Trevisan MT, Caramaschi P, Bambara LM, Corrocher R. Correlations between the intensity of fMLP-dependent respiratory burst and cellular fatty acid composition in human neutrophils. Br J Haematol1995; 89:271–6.[ISI][Medline]
34. Pope RM. Immunoregulatory mechanisms present in the maternal circulation during pregnancy. Baillieres Clin Rheumatol1990; 4:33–52.[Medline]
35. Stimson WH. Are pregnancy-associated serum proteins responsible for the inhibition of lymphocyte transformation by pregnancy serum? Clin Exp Immunol1980; 40:157–60.[ISI][Medline]
36. Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today1997; 18:478–82.[ISI][Medline]
37.
Wallace FA, Miles EA, Evans C, Stock TE, Yaqoob P, Calder PC. Dietary fatty acids influence the production of Th1- but not Th2-type cytokines. J Leukoc Biol2001; 69:449–57.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  I Crocker, N Lawson, and J Fletcher Effect of pregnancy and obstructive jaundice on inflammatory diseases: the work of P S Hench revisited Ann Rheum Dis, April 1, 2002; 61(4): 307 - 310. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||