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Age Associated Alterations in Costimulatory and Adhesion Molecule Expression in Lupus-Prone Mice Are Attenuated by Food Restriction with n-6 and n-3 Fatty Acids

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Abstract

Costimulatory and adhesion molecules are known to play a major role in the pathogenesis of systemic lupus erythematosus. Since fish oil and calorie restriction have been reported to attenuate the development of disease in lupus prone (NZBxNZW)F1 mice, the objective of this study was to assess the expression of these key inflammatory molecules in these mice fed diets differing in n-6 and n-3 fatty acid content and fed either food restricted or ad libitum. Age-associated increases in the expression of CD28, ICAM-1, and PGP-1 molecules that are involved in the recruitment of inflamed lymphocytes into the kidney were attenuated in mice restricted in food intake. The increase in costimulatory (CD80 and CD86) and adhesion (ICAM-1, PGP-1, LFA-1, and Mac-1) in peripheral blood mononuclear cells was also attenuated by food restriction and to a lesser extent by fish oil alone. Interestingly, amelioration of lupus (laminin expression and proteinuria) correlated with the above beneficial effects and could be seen even in 24-month-old mice. In summary, food restriction and fish oil delay the onset of lupus disease and increase life span in B/W mice by prolonging the maintenance of a youthful immune phenotype.

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REFERENCES

  1. Theofilopoulos AN, Dixon FJ: Murine models of systemic lupus erythematosus. Adv Immunol 37:269–390, 1985

    PubMed  Google Scholar 

  2. Chiang B, Bearer E, Ansari A, Dorshkind K, Gershwin ME: The BM12 mutation and autoantibodies to dsDNA in NZB.H-2 bm12 mice. J Immunol 145:94–101, 1990

    PubMed  Google Scholar 

  3. Springer TA: Traffic signals for lymphocyte recirculation and leuko-cyte emigration: The multistep paradigm. Cell 76:301–314, 1994

    Article  PubMed  Google Scholar 

  4. Butcher EC: Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity. Cell 67:1033–1036, 1991

    PubMed  Google Scholar 

  5. Lasky LA: Selectins: Interpreters of cell-specific carbohydrate in-formation during inflammation. Science 258:964–969, 1992

    PubMed  Google Scholar 

  6. Mulligan MS, Johnson KJ, Todd RFD, Issekutz TB, Miyasaka M, Tamatani T, Smith CW, Anderson DC, Ward PA: Requirements for leukocyte adhesion molecules in nephrotoxic nephritis. J Clin Invest 91:577–587, 1993

    PubMed  Google Scholar 

  7. Wuthrich RP: Cell adhesion molecules and inflammatory renal dis-eases [editorial]. Nephrol Dial Transplant 9:1063–1065, 1994

    PubMed  Google Scholar 

  8. Diaz Gallo C, Jevnikar AM, Brennan DC, Florquin S, Pacheco-Silva A, Kelley VR: Autoreactive kidney-infiltrating T-cell clones in murine lupus nephritis. Kidney Int 42:851–859, 1992

    PubMed  Google Scholar 

  9. Wuthrich RP, Jevnikar AM, Takei F, Glimcher LH, Kelley VE: In-tercellular adhesion molecule-1 (ICAM-1) expression is upregulated in autoimmune murine lupus nephritis. Am J Pathol 136:441–450, 1990

    Google Scholar 

  10. Kawasaki K, Yaoita E, Yamamotya T, Tamatani T, Miyasaka M, Kihara I: Antibodies against intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 prevent glomerular in-jury in rat experimental crescentic glomerulonephritis. J Immunol 150:1074–1083, 1993

    PubMed  Google Scholar 

  11. Nishikawa K, Guo YJ, Miyasaka M, Tamatani T, Collins AB, Sy MS, McCluskey RT, Andres G: Antibodies to intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 prevent cres-cent formation in rat autoimmune glomerulonephritis. J Exp Med 177:667–677, 1993

    PubMed  Google Scholar 

  12. Bullard DC, King PD, Hicks MJ, Dupont B, Beaudet AL, Elkon KB: Intercellular adhesion molecule-1 deficiency protects MRL/MpJ-Fas( lpr) mice from early lethality. J Immunol 159:2058–2067, 1997

    PubMed  Google Scholar 

  13. Ledbetter JA, Imboden JB, Schieven GL, Grosmaire LS, Rabi-novitch PS, Lindsten T, Thompson CB, June CH: CD28 ligation in T-cell activation: Evidence for two signal transduction pathways. Blood 75:1531–1539, 1990

    PubMed  Google Scholar 

  14. Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, Damle NK: Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 176:1595–1604, 1992

    PubMed  Google Scholar 

  15. Thompson CB, Lindsten T, Ledbetter JA, Kunkel SL, Young HA, Emerson SG, Leiden JM, June CH: CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/ cytokines. Proc Natl Acad Sci USA 86:1333–1337, 1989

    PubMed  Google Scholar 

  16. Lindsten T, Lee K, Harris E, Petryniak B, Craighead N, Reynolds P, Lombard D, Freeman G, Nadler L, Gray G: Characterization of CTLA-4 structure and expression on human T cells. J Immunol 151:3489–3499, 1993

    PubMed  Google Scholar 

  17. Linsley P, Brady W, Urnes M, Grosmaire L, Damle N, Ledbetter J: CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174:561–569, 1991

    PubMed  Google Scholar 

  18. Shahinian A, Pfeffer K, Lee K, Kundig T, Kishihara K, Wakeham A, Kawai K, Ohashi P, Thompson C, Mak T: Differential T cell costim-ulatory requirements in CD28-deficient mice. Science 261:609–612, 1993

    PubMed  Google Scholar 

  19. Klaus SJ, Pinchuk LM, Ochs HD, Law CL, Fanslow WC, Armitage RJ, Clark EA: Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction. J Immunol 152:5643–5652, 1994

    PubMed  Google Scholar 

  20. Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, Singh C, Tepper MA: Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257:792–795, 1992

    PubMed  Google Scholar 

  21. Perrin PJ, Scott D, Quigley L, Albert PS, Feder O, Gray GS, Abe R, June CH, Racke MK: Role of B7:CD28/CTLA-4 in the induc-tion of chronic relapsing experimental allergic encephalomyelitis. J Immunol 154:1481–1490, 1995

    PubMed  Google Scholar 

  22. Akalin E, Chandraker A, Sayegh M, Turka LA: Role of the CD28:B7 costimulatory interaction in alloimmune responses. Kidney Int Suppl 58:S8–S10, 1997

    PubMed  Google Scholar 

  23. Gallon L, Chandraker A, Issazadeh S, Peach R, Linsley PS, Turka LA, Sayegh MH, Khoury SJ: Differential effects of B7-1 block-ade in the rat experimental autoimmune encephalomyelitis model. J Immunol 159:4212–4216, 1997

    PubMed  Google Scholar 

  24. Webb LM, Walmsley MJ, Feldmann M: Prevention and amelio-ration of collagen-induced arthritis by blockade of the CD28 co-stimulatory pathway: Requirement for both B7-1 and B7-2. Eur J Immunol 26:2320–2328, 1996

    PubMed  Google Scholar 

  25. Jolly CA, Fernandes G: Diet modulates Th-1 and Th-2 cytokine pro-duction in the peripheral blood of lupus-prone mice. J Clin Immunol 19:172–178, 1999

    PubMed  Google Scholar 

  26. Muthukumar AR, Jolly CA, Zaman K, Fernandes G: Calorie restric-tion decreases proinflammatory cytokines and polymeric Ig recep-tor expression in the submandibular glands of autoimmune prone (NZB x NZW)F1 mice. J Clin Immunol 20:354–361, 2000

    PubMed  Google Scholar 

  27. Muthukumar A, Zaman K, Lawrence R, Barnes JL, Fernandes G: Food restriction and fish oil suppress atherogenic risk factors in lupus prone (NZB x NZW)F1 mice. J Clin Immunol 23:23–33, 2003

    PubMed  Google Scholar 

  28. Venkatraman JT, Chandrasekar B, Kim JD, Fernandes G: Effects of n-3 and n-6 fatty acids on the activities and expression of hepatic antioxidant enzymes in autoimmune-prone NZBxNZW F1 mice. Lipids 29:561–568, 1994

    PubMed  Google Scholar 

  29. Chandrasekar B, McGuff HS, Aufdermorte TB, Troyer DA, Talal N, Fernandes G: Effects of calorie restriction on transforming growth factor beta 1 and proinflammatory cytokines in murine Sjogren's syndrome. Clin Immunol Immunopathol 76:291–296, 1995

    PubMed  Google Scholar 

  30. Reeves PG, Nielsen FH, Fahey GC, Jr: AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951, 1993

    PubMed  Google Scholar 

  31. Jolly C, Muthukumar A, Reddy Avula C, Troyer D, Fernandes G: Life span is prolonged in food-restricted autoimmune-prone (NZB x NZW)F(1) mice fed a diet enriched with (n-3) fatty acids. J Nutr 131:2753–2760, 2001

    PubMed  Google Scholar 

  32. Kootstra CJ, Van Der Giezen DM, Van Krieken JH, De Heer E, Bruijn JA: Effective treatment of experimental lupus nephritis by combined administration of anti-CD11a and anti-CD54 antibodies. Clin Exp Immunol 108:324–332, 1997

    PubMed  Google Scholar 

  33. Roy-Chaudhury P, Wu B, King G, Campbell M, Macleod AM, Haites NE, Simpson JG, Power DA: Adhesion molecule interactions in human glomerulonephritis: Importance of the tubulointerstitium. Kidney Int 49:127–134, 1996

    PubMed  Google Scholar 

  34. Funauchi M, Ohno M, Minoda M, Horiuchi A: Abnormal expression of intercellular adhesion molecule-1 on peripheral blood mononu-clear cells from patients with systemic lupus erythematosus. J Clin Lab Immunol 40:115–124, 1993

    PubMed  Google Scholar 

  35. Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA: Induction by IL 1 and interferon-gamma: Tissue distribution, bio-chemistry, and function of a natural adherence molecule (ICAM-1). J Immunol 137:245–254, 1986

    PubMed  Google Scholar 

  36. Nikolic-Paterson DJ, Lan HY, Hill PA, Vannice JL, Atkins RC: Sup-pression of experimental glomerulonephritis by the interleukin-1 receptor antagonist: Inhibition of intercellular adhesion molecule-1 expression. J Am Soc Nephrol 4:1695–1700, 1994

    PubMed  Google Scholar 

  37. Fuggle SV, Sanderson JB, Gray DW, Richardson A, Morris PJ: Vari-ation in expression of endothelial adhesion molecules in pretrans-plant and transplanted kidneys—Correlation with intragraft events. Transplantation 55:117–123, 1993

    PubMed  Google Scholar 

  38. Ootaka T, Saito T, Soma J, Yusa A, Abe K: Intercellular adhesion molecule-1/leukocyte function associated antigen-1-mediated and complement receptor type 4-mediated infiltration and activation of glomerular immune cells in immunoglobulin A nephropathy. Am J Kidney Dis 28:40–46, 1996

    PubMed  Google Scholar 

  39. Davis GE: The Mac-1 and p150,95 beta 2 integrins bind denatured proteins to mediate leukocyte cell-substrate adhesion. Exp Cell Res 200:242–252, 1992

    PubMed  Google Scholar 

  40. Freyer DR, Morganroth ML, Todd RFd: Surface Mo1 (CD11b/CD18) glycoprotein is up-modulated by neutrophils recruited to sites of inflammation in vivo. Inflammation 13:495–505, 1989

    PubMed  Google Scholar 

  41. Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA: Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 173:721–730, 1991

    PubMed  Google Scholar 

  42. Lin H, Bolling SF, Linsley PS, Wei RQ, Gordon D, Thompson CB, Turka LA: Long-term acceptance of major histocompatibility com-plex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion. J Exp Med 178:1801–1806, 1993

    PubMed  Google Scholar 

  43. Lenschow DJ, Ho SC, Sattar H, Rhee L, Gray G, Nabavi N, Herold KC, Bluestone JA: Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J Exp Med 181:1145–1155, 1995

    PubMed  Google Scholar 

  44. Feher MD: Lipid lowering to delay the progression of coronary artery disease. Heart 89:451–458, 2003

    PubMed  Google Scholar 

  45. Tada Y, Nagasawa K, Ho A, Morito F, Koarada S, Ushiyama O, Suzuki N, Ohta A, Mak TW: Role of the costimulatory molecule CD28 in the development of lupus in MRL/lpr mice. J Immunol 163:3153–3159, 1999

    PubMed  Google Scholar 

  46. Vallejo AN, Nestel AR, Schirmer M, Weyand CM, Goronzy JJ: Aging-related deficiency of CD28 expression in CD4 +T cells is as-sociated with the loss of gene-specific nuclear factor binding activity. J Biol Chem 273:8119–8129, 1998

    PubMed  Google Scholar 

  47. Merino J, Martinez-Gonzalez MA, Rubio M, Inoges S, Sanchez-Ibarrola A, Subira ML: Progressive decrease of CD8high +CD28 +CD57-cells with ageing. Clin Exp Immunol 112:48–51, 1998

    PubMed  Google Scholar 

  48. Lenschow DJ, Walunas TL, Bluestone JA: CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233–258, 1996

    PubMed  Google Scholar 

  49. Bendich A: Recent advances in clinical research involving carotenoids. Clin Appl Nutr 1:14–22, 1994

    Google Scholar 

  50. Schwarting A, Tesch G, Kinoshita K, Maron R, Weiner HL, Kelley VR: IL-12 drives IFN-gamma-dependent autoimmune kid-ney disease in MRL-Fas(lpr) mice. J Immunol 163:6884–6891, 1999

    PubMed  Google Scholar 

  51. Sauty A, Dziejman M, Taha RA, Iarossi AS, Neote K, Garcia-Zepeda EA, Hamid Q, Luster AD: The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells. J Immunol 162:3549–3558, 1999

    PubMed  Google Scholar 

  52. Menten P, Proost P, Struyf S, Van Coillie E, Put W, Lenaerts JP, Conings R, Jaspar JM, De Groote D, Billiau A, Opdenakker G, Van Damme J: Differential induction of monocyte chemotactic protein-3 in mononuclear leukocytes and fibroblasts by interferon-alpha/beta and interferon-gamma reveals MCP-3 heterogeneity. Eur J Immunol 29:678–685, 1999

    PubMed  Google Scholar 

  53. Liang B, Kashgarian MJ, Sharpe AH, Mamula MJ: Autoantibody responses and pathology regulated by B7-1 and B7-2 costimulation in MRL/lpr lupus. J Immunol 165:3436–3443, 2000

    PubMed  Google Scholar 

  54. Mikecz K, Brennan FR, Kim JH, Glant TT: Anti-CD44 treatment ab-rogates tissue oedema and leukocyte infiltration in murine arthritis. Nat Med 1:558–563, 1995

    PubMed  Google Scholar 

  55. Benz PS, Fan X, Wuthrich RP: Enhanced tubular epithelial CD44 expression in MRL-lpr lupus nephritis. Kidney Int 50:156–163, 1996

    PubMed  Google Scholar 

  56. Fung TT, Willett WC, Stampfer MJ, Manson JE, Hu FB: Dietary patterns and the risk of coronary heart disease in women. Arch Intern Med 161:1857–1862, 2001

    PubMed  Google Scholar 

  57. Simopoulos AP: Omega-3 fatty acids in inflammation and autoim-mune diseases. J Am Coll Nutr 21:495–505, 2002

    PubMed  Google Scholar 

  58. Simopoulos AP: Evolutionary aspects of diet and essential fatty acids. World Rev Nutr Diet 88:18–27, 2001

    PubMed  Google Scholar 

  59. Harris WS: Nonpharmacologic treatment of hypertriglyceridemia: Focus on fish oils. Clin Cardiol 22:II40–II43, 1999

    PubMed  Google Scholar 

  60. Harper C, Jacobson T: The fats of life: The role of omega-3 fatty acids in the prevention of coronary heart disease. Arch Intern Med 161:2185–2192, 2001

    PubMed  Google Scholar 

  61. Nordoy A, Bonaa KH, Sandset PM, Hansen JB, Nilsen H: Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipemia in patients with combined hyperlipemia. Arterioscler Thromb Vasc Biol 20:259–265, 2000

    PubMed  Google Scholar 

  62. De Lorgeril M, Salen P: Fish and N-3 fatty acids for the prevention and treatment of coronary heart disease: Nutrition is not pharmacol-ogy. Am J Med 112:316–319, 2002

    PubMed  Google Scholar 

  63. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J: Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 346:1113–1118, 2002

    PubMed  Google Scholar 

  64. Cleland LG, James MJ: Rheumatoid arthritis and the balance of dietary N-6 and N-3 essential fatty acids. Br J Rheumatol 36:513–514, 1997

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Clinical Immunology, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas

    Alagarraju Muthukumar, Dongxu Sun, Khaliquz Zaman & Gabriel Fernandes

  2. Division of Renal Disease, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas

    J. L. Barnes

  3. Division of Hematology, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas

    David Haile

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  1. Alagarraju Muthukumar
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  2. Dongxu Sun
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Muthukumar, A., Sun, D., Zaman, K. et al. Age Associated Alterations in Costimulatory and Adhesion Molecule Expression in Lupus-Prone Mice Are Attenuated by Food Restriction with n-6 and n-3 Fatty Acids. J Clin Immunol 24, 471–480 (2004). https://doi.org/10.1023/B:JOCI.0000040918.92219.d1

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