Title: Membrane Composition
Key words: PUFA, polyunsaturated
fatty acids, phospholipid, cell membranes, linolenic acid, prostaglandins, cytokines,
eicosanoids, fish oil, anti-inflammatory
Date: Dec 1999
Category: 6. The Body
Author: Dr van Rhijn
Membrane Composition and Inflammation
Lipid soluble polyunsaturated fatty acids (PUFAs) are
integral components of complex phospholipid bilayer cellular membranes, modulating
fluidity1, signalling pathways, enzymes, messengers and receptors
involved in immune responses. Both n-3 and n-6 series PUFA's have immunomodulatory
potential in illnesses and the potential sites for interaction lie within cell
Polyunsaturated Fatty Acids (PUFA's)
Dietary n-6 parent fatty acid, linoleic acid (LA, C18:2
w -6), passes through sequential steps of desaturation
and elongation3 to produce g -linolenic
acid (GLA, C18:3 w -6 ) 4, dihomogammalinolenic
acid (DHGLA, C20:3 w -6) and arachidonic acid
(AA, C20:4 w -6).
In contrast, the parent n-3 fatty acid, a
-linolenic acid (ALA, C18:3 w -3) produces the
longer chain eicosapentaenoic acid (EPA, C20:5 w
-3) and docosahexaenoic acid (DHA, 22:6 w -3)
5. The major PUFA's incorporated into cell membranes are the 20 carbon
AA and EPA (highest affinity6) which are metabolised into biologically
active eicosanoids7 by cyclooxygenases to prostanoids [prostaglandins
(PG's) and thromboxanes (TX's)], and by lipoxygenases into leucotrienes (LT's).
AA (n-6) is the major precursor for the 2-series TX's
& PG's and the 4-series LT's, whereas EPA (n-3) produces the 3-series TX's
& PG's and the 5-series LT's8. ALA and LA compete for metabolic
enzymes and a proper balance is essential to optimise the n-3 and n-6 content
of cell membranes9.
PG's and LT's play key roles as inflammatory modulators
by influencing the production of cytokines10, 11, ultimately controlled
by dietary and membrane incorporated PUFA's.
The PG3 & LT5 series12, derived from n-3
PUFA's (EPA), are 100-fold less potent biologically than the LT4 series from
n-6 PUFA's (AA) with which they compete for cellular binding sites and are associated
with decreased inflammatory responses13.
PA competitively inhibits AA metabolism and
displaces AA14 from cell membrane phospholipids, thus reducing the
biosynthesis of pro-inflammatory eicosanoids15, 16.
N-3 PUFA (fish oils) exert a generalised anti-inflammatory17
influence, by reducing cytokine (TNF a
18, IL-1b 19, IL-1a
20, IL-221 and IL-622, 23) production24
by mononuclear cells. Fish oil-fed animals had less fever in response to IL-1
(guinea-pigs)25, murine macrophages showed decreased TNF26
and IL-6 production27, exhibited a lesser degree of anorexia in response
to IL-1 (rats)28 or TNF29 compared to other oils. EPA
and coconut oil (low in LA) fed to rats, resulted in high lateral fluidity (peritoneal
macrophages & hepatocytes) and suppressed pro-inflammatory cytokine production
(TNF30 & IL-131) and responsiveness of tissue to inflammatory
Other fats (butter, olive & maize) had opposing effects32.
EPA also altered the leukotriene ratio LTB4/LTB5 towards an anti-inflammatory
one by increasing LTB5 levels (patients with major surgery)33. Fish
oil also diminished lymphocyte proliferation34, T-cell-mediated cytotoxicity35,
natural killer cell activity, macrophage-mediated cytotoxicity, monocyte and
neutrophil chemotaxis, major histocompatibility class II expression and antigen
presentation, adhesion molecule expression36 and C-reactive protein
Dietary intake of PUFAs leads to changes in the fatty
acid composition of cell membranes and the balance of AA: EPA is particularly
important, as it influences the type and biological efficacy of eicosanoids
controlling inflammatory responses37.
- Escudero, A. et al. Effect of dietary (n-9),
(n-6) and (n-3) fatty acids on membrane lipid composition and morphology
of rat erythrocytes. Biochem. Biophys. Acta. 1998; 1394: 65 73.
- Ross, J.A. et al. The anti-catabolic effects
of n-3 fatty acids. Curr. Opin. Clin. Nutr. Metab. Care. 1999; 2: 219 -
- Calder, P.C. Bioactive lipids in foods. Bioch. Soc.
Trans. 1996; 24: 814 824.
- Gazso, A. et al. Effects of omega-3 fatty
acids on the prostaglandin system in healthy probands. Wien. Klin. Woch.
1989; 101: 283 288.
- Roche, H. Unsaturated fatty acids. Proc. Nutr. Soc.
1999; 58: 391 401.
- Murphy, M.G. Dietary fatty acids and membrane function.
J. Nutr. Bioch. 1990; 1: 68 - 79.
- Johnson, M.M. et al. Dietary supplementation
with g -linolenic acid alters fatty acid
content and eicosanoids production in healthy humans. J. Nutr. 1997; 127:
- Rose, D. Dietary fatty acids and cancer. Am. J.
Clin. Nutr. 1997; 66(Supp). 998S 1003S.
- Okuyama, H. et al. Dietary fatty acids
the n-6/n-3 balance and chronic elderly disease. Excess linoleic acid and
relative n-3 deficiency syndrome seen in Japan. Prog. Lipid Res. 1997; 35:
- Williams, J.A. & Shacter, E. Regulation of macrophage
cytokine production by prostaglandin E2 distinct roles of cyclooxygenases-1
and 2. J. Biol. Chem. 1997; 272: 25693 25699.
- Rola-Pleszczynski, M. & Stankova, J. Cytokine
gene regulation by PGE2, LTB4 and PAF. Mediators of Inflammation. 1992;1:
5 - 8.
- Miles, E.A. & Calder, C. Modulation of immune
function by dietary fatty acids. Proc. Nutr. Soc. 1998; 57: 277 - 292.
- Alexander, J.W. Immunonutrition: the role of w
-3 fatty acids. Nutrition. 1998; 14: 627 633.
- Luostarinen, R. & Saldeen, T. Dietary fish oil
decreases superoxide generation by human neutrophils: Relation to cyclooxygenases
pathway and lysosomal enzyme release. Prostag. Leukotr. & Ess. Fatty
Acids. 1996; 55, 3: 167 172.
- Calder, P.C. N-3 polyunsaturated fatty acids and
immune cell function. Adv. Enzyme Regul. 1997; 37, 197 237.
- Shimizu, T. et al. Enzyme with dual lipoxygenase
activities catalyzes leukotriene A4 synthesis from arachidonic acid. Proc.
Natl. Acad. Sci. USA. 1984; 81: 689 693.
- Wallace, J.M. et al. dietary fish oil supplementation
alters leukocyte function and cytokine production in healthy women, Arterioscl.
Thromb. Vascul. Biol. 1995; 15: 185 189.
- Endres, S. et al. The effect of dietary supplementation
with n-3 polyunsaturated fatty acids on the synthesis of IL-1 and TNFa
by mononuclear cells. N. Eng. J. Med. 1989; 320: 265 - 271.
- Caughey, G.E. et al. The effect on human
tumor necrosis factor a and interleukin 1b
production of diets enriched in n-3 fatty acids from vegetable oil or fish
oil. Am. J. Clin. Nutr. 1996; 57: 65 - 68.
- Bonner, S.A. et al. Eicosapentaenoic acid
supplementation modulates the immune responsiveness of human blood. Prostaglan.
Leucotr. Essen. Fatty Acids. 57(2): 224, abs
- Jolly, C.A. et al. Dietary (n-3) polyunsaturated
fatty acids suppress murine lymphoproliferation, interleukin-2 secretion
and the formation of diacylglycerol and ceramide. J. Nutr. 1997; 127: 37
- Wigmore, S.J. et al. Down-regulation of the
acute-phase response in patients with pancreatic cancer cachexia receiving
oral eicosapentaenoic acid is mediated via suppression of interleukin-6.
Clin. Sci. 1997c; 92: 215 221.
- Tappia, P.S. & Grimble, R.F. The relationship
between altered membrane composition, eikosanoids and TNF-induced IL1 and
IL6 production in macrophages of rats fed fats of different unsaturated
fatty acid composition. Mol. Cell. Bioch. 1996; 165: 135 - 143.
- Meydani, S.N. effect of (n-3) polyunsaturated fatty
acids on cytokine production and their biologic function. Nutrition. 1996;
12: S8 14.
- Pomposelli, J.J. et al. Attenuation of the
febrile response in guinea pigs by fish oil enriched diets. J. Parent. Enter.
Nutr. 1989; 13: 136 - 140.
- Wallace, F.A. et al. Dietary fish oil decreases
the production of pro-inflammatory mediators by murine macrophages. Proc.
Nutr. Soc. 1998; 57: 50A
- Yaqoob, P. & Calder, P.C. Effects of dietary
lipid manipulation upon inflammatory mediator production by murine macrophages.
Cell. Immunol. 1995b; 163:120 - 128.
- Hellersteiner, M.K. et al. Interleukin-1-induced
anorexia in the rat. Influence of prostaglandins. J. Clin. Invest. 1989;
84: 228 - 235.
- Mulrooney, M.G. & Grimble, R.F. The influence
of butter, and corn, coconut and fish oils on the effects of recombinant
human tumour necrosis factor a in rats. Clin.
Sci. 1993; 84: 105 - 112.
- Calder, P.C. n-3 Polyunsaturated fatty acids and
cytokine production in health and disease. Ann. Nutr. Metab. 1997; 41: 203
- Meydani, S.N. et al. Immunologic effects
of National Cholesterol Education Panel Step-2 diets with and without fish-derived
n-3 polyunsaturated fatty acid enrichment. J. Clin. Invest. 1993; 92: 105
- Tappia, P.S. et al. The influence of membrane
fluidity, TNF receptor binding cAMP production and GTPase activity on macrophage
cytokine production in rats fed on fat diets. Mol. Cell. Bioch. 1997; 166:
135 - 143.
- Wachtler, P. et al. Influence of a total
parenteral nutrition enriched with w -3
fatty acids on leukotriene synthesis of peripheral leukocytes and systemic
cytokine levels in patients with major surgery. J. of Trauma. 1997; 42:
191 - 198.
- Yaqoob, P. & Calder, P.C. The effects of dietary
lipid manipulation on the production of murine T cell-derived cytokines.
Cytokine, 1995; 7,6: 548 453.
- Calder, P.C. Dietary fatty acids and the immune
system. Nutr. Rev. 1998; 56: S70 83.
- Calder, P.C. Immunoregulatory and anti-inflammatory
effects of n-3 polyunsaturated fatty acids. Braz. J. Med. Biol. Res. 1998;
31, 4: 467 490.
- Grimble, R.F. Dietary lipids and the inflammatory
response. Proc. Nutr. Soc. 1998; 57: 535 - 542.