Research Program:

Immune Suppression by Cigarette Smoke: Cigarette smoking causes profound suppression of T and B cell responses in the lungs and lung-associated lymph nodes. We have identified two classes of compounds in cigarettes smoke that block T cell activation and proliferation. Acrolein and crotonaldehyde are volatile, thiol-reactive aldehydes present in the gas phase of cigarette smoke. They suppress production of several proinflammatory cytokines, including IL-1b, IL-2, TNF-a and IFN-g by inhibiting the induction of NF-kB and AP-1 DNA binding activity. Hydroquinone and catechol are phenolic components of cigarette tar that block lymphocyte proliferation by quenching the tyrosyl radical in ribonucleotide reductase. In addition, they independently alter induction of several cell cycle regulatory proteins, including CDK1 and Rb. Current research focuses on elucidating the underlying molecular events behind these phenomena.

Selected References:

• Li Q, Geiselhart L, Mittler J, Mudzinski S, Lawrence DA, Freed BM. Inhibition of human T lymphoblast proliferation by hydroquinone. Tox Appl Pharmacol 139:317, 1996.
• Geiselhart LA, Christian T, Minnear F, Freed BM. The cigarette tar component p-benzoquinone blocks T lymphocyte activation by inhibiting interleukin-2 production, but not CD25, ICAM-1 or LFA-1 expression. Tox Appl Pharmacol 143:30, 1997.
• Li Q, Aubrey MT, Christian T, Freed BM. Differential inhibition of DNA synthesis in human T cells by the cigarette tar components hydroquinone and catechol. Fund Appl Toxicol (now Toxicol Sciences) 38:158, 1997.
• Li Q, Kasten-Jolly J, Yen Y, Freed BM. Reversal of hydroquinone-mediated suppression of T cell proliferation by transfection of the M2 subunit of ribonucleotide reductase. Tox Appl Pharmacol 150:154, 1998.
• Ouyang Y, Virasch N, Hao P, Aubrey MT, Mukerjee N, Bierer BE, Freed BM. Suppression of human IL-1(, IL-2, IFN-( and TNF-( by cigarette smoke extracts. J Allergy Clin Immunology 106:280, 2000.
• McCue JM, Link KL, Eaton SS, Freed BM. Exposure to cigarette tar inhibits ribonucleotide reductase and blocks lymphocyte proliferation. J Immunol 165:6771, 2000.
• Freed BM, Ouyang Y, McCue JM. Mechanisms of altered transcription by cigarette smoke. Toxicol Sciences 59:1, 2001.
• McCue JM, Lazis S, Modiano J, Freed BM. Hydroquinone and catechol interfere with T cell cycle entry and progression through the G1 phase. Mol Immunol 39:995, 2003.
• Lambert C, McCue J, Portas M, Ouyang Y, Li J, Rosano TG, Lazis A, Freed BM. Acrolein in cigarette smoke inhibits T cell activation. J Allergy Clin Immunology 116:916, 2005.
• Frazer-Abel A, McCue J, Lazis S, Portas M, Lambert C, Freed BM. Cigarette tar phenols impede T cell cycle progression by inhibiting cyclin-dependent kinases. Mol Immunol, 2006 (in press).
  

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