title: Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin.
abstract: Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell-mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in nonobese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.
authors: Department of Immunology,  Weizmann Institute of Science, Rehovot 76100,  Israel.
authors: Felix
authors: F
authors: Mor
authors: Irun R
authors: IR
authors: Cohen
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D011485:Protein Binding; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D047090:beta-Lactams / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000418:Albumins; D000900:Anti-Bacterial Agents; D047090:beta-Lactams
references: Stroke. 2004 Feb;35(2):590-5
references: 14726550
references: J Immunol. 2005 Sep 1;175(5):3439-45
references: 16116239
references: Arthritis Rheum. 2000 Nov;43(11):2583-9
references: 11083284
references: FEBS Lett. 1990 Apr 24;263(2):237-40
references: 2335227
references: Annu Rev Biochem. 1983;52:825-69
references: 6351730
references: Nature. 2005 Jan 6;433(7021):73-7
references: 15635412
references: Am J Phys Med Rehabil. 1995 Nov-Dec;74(6):415-8
references: 8534384
references: Nature. 2007 Jul 26;448(7152):484-487
references: 17581588
references: Exp Cell Res. 1993 Jun;206(2):255-60
references: 7684695
references: Arch Dis Child. 1982 Jan;57(1):59-62
references: 7065695
references: Biochim Biophys Acta. 2001 Jan 12;1544(1-2):386-92
references: 11341948
references: Ann Neurol. 2004 Mar;55(3):410-7
references: 14991819
references: Gut. 2005 Nov;54(11):1546-52
references: 15987795
references: Cancer Res. 2004 Nov 1;64(21):8085-92
references: 15520220
references: Diabetes. 1997 May;46(5):758-64
references: 9133541
references: Aliment Pharmacol Ther. 2002 Dec;16 Suppl 5:6-11
references: 12423448
references: Nat Rev Immunol. 2007 Jun;7(6):443-53
references: 17525753
references: J Mol Biol. 2005 Oct 14;353(1):38-52
references: 16169013
references: J Biol Chem. 1988 Aug 15;263(23):11436-42
references: 2457023
references: Int J Biochem Cell Biol. 2005 Apr;37(4):765-74
references: 15694836
references: J Leukoc Biol. 1999 May;65(5):707-14
references: 10331502
references: J Neuroimmunol. 2006 May;174(1-2):108-18
references: 16564577
references: DNA Cell Biol. 2006 Jul;25(7):393-8
references: 16848680
references: J Clin Invest. 1993 Nov;92(5):2199-206
references: 7693759
references: J Immunol. 2002 Sep 15;169(6):3422-8
references: 12218165
references: Protein Sci. 2005 Sep;14(9):2469-77
references: 16081656
references: Proteomics. 2007 Jun;7(12):2019-37
references: 17514683
references: J Dairy Sci. 2005 Feb;88(2):569-76
references: 15653522
references: J Neurol Neurosurg Psychiatry. 1998 Jun;64(6):736-41
references: 9647301
references: Hum Reprod. 2006 Mar;21(3):645-50
references: 16253963
references: Am J Physiol Renal Physiol. 2007 May;292(5):F1464-70
references: 17213467
references: Immunity. 2001 Jul;15(1):15-22
references: 11485734
references: Antimicrob Agents Chemother. 1976 May;9(5):741-7
references: 949172
references: Biochem Pharmacol. 1987 Oct 15;36(20):3379-85
references: 3675600
references: Am J Physiol Lung Cell Mol Physiol. 2004 May;286(5):L1016-26
references: 14729511
references: J Cell Biochem. 2003 May 15;89(2):356-63
references: 12704798
references: Axone. 1998 Jun;19(4):67-70
references: 9849133
references: Nat Med. 1998 Jan;4(1):78-83
references: 9427610
references: Int Arch Allergy Appl Immunol. 1985;76(1):42-6
references: 2578436
references: J Clin Invest. 1990 May;85(5):1594-8
references: 2110191
references: Eur J Pharmacol. 2005 Sep 27;520(1-3):1-11
references: 16153637
references: Eur J Immunol. 2002 Feb;32(2):356-65
references: 11807775
references: DNA Cell Biol. 2006 Jan;25(1):63-8
references: 16405401
references: Blood. 2003 Apr 15;101(8):3174-80
references: 12480711
references: Annu Rev Immunol. 2005;23:447-85
references: 15771578