Thomas M. Petro, PhD

Professor of Microbiology and Immunology Dept. Oral Biology University of Nebraska Medical Center College of Dentistry 40th and Holdrege Lincoln, NE 68583-0740 402-472-1327 Fax: 402-472-2551 tpetro@unmc.edu

Research Interests:

The main focus of my laboratory has been the induction of the IL-12 family of cytokines during the innate immune response to viruses. The innate immune response to viral infection is dependent to a large extent upon the induction of Type I interferons (IFN) alpha/beta, IL-12, and IFN-_. Type I interferons create an antiviral state in which protein kinase R, ISG15, ISG54 and IP-10 are produced and the cytotoxic capabilities of NK and NKT cells against virus-infected cells are increased. On the other hand, IL-12 and IFN-gamma increase the proliferation of NK and NKT cells and bring about the expression of inducible nitric oxide synthase (NOS2) and thus nitric oxide, which has potent anti-viral properties. Interestingly, innate anti-viral immunity is internally regulated by Type I interferon control of the IL-12/IFN-gamma/NOS2 nexus and nitric oxide control of Type I interferon expression. Therefore it is possible that one or the other system will dominate an innate anti-viral immune response.

The immune response to viruses is considered necessary for the control of viral replication within the human body. Nevertheless, it has been observed that the tissue destruction brought about by the virus sometimes leads to an autoimmune response against proteins in the body during the adaptive immune response phase of the immune response to the virus. Occasionally, this autoimmune response leads to a chronic autoimmune disease state, such as multiple sclerosis. It is not completely clear what triggers the autoimmune disease during the adaptive phase of the immune response, but production of the IL-12 family of proteins precedes and dominates many of these autoimmune responses. We have found that in an experimental mouse model that the production of this IL-12 family of cytokines is a normal and necessary part of the anti-viral innate immune response. The molecular mechanism by which the IL-12 family of proteins is expressed at the gene level is not known and is the subject of our research. We have and will be examining the role of the IL-12 family of proteins in the induction of nitric oxide (NO), which could cause some of the tissue destruction associated with autoimmune disease but is also part of the normal innate anti-viral immune response.

Selected Publications:

1. Vaidyanathan H, Zhou Y, Petro TM, and Schwartzbach SD. Intracellular localization of the p35 subunit of murine IL-12. Cytokine, 21:120-128, 2003

2. Petro TM. Modulation of IL-12 p35 and p40 promoter activity by smokeless tobacco extract is associated with an effect upon activation of NF-kB but not IRF transcription factors. International Immunophpharmacology 3:735-745, 2003.

3. Petro TM, Anderson LL, Gowler JS, Liu X, and Schwartzbach SD. Smokeless tobacco extract decreases IL-12 production from LPS-stimulated but decreases IL-12 from IFN-_-stimulated macrophages. International Immunopharmacology. 2:345-355, 2002.

4. Kollet J, Witek C, Gentry JD, Liu X, Schwartzbach SD, and Petro TM. Deletional analysis of the murine IL-12 p35 promoter comparing interferon-_ and LPS stimulation. J. Immunol.167:5653-5663, 2001.

5. Vaidyanathan H, Gentry JD, Weatherman A, Schwartzbach SD, and Petro TM. Differential response of the murine IL-12 p35 gene to lipopolysaccharide compared with interferon-gamma and CD40 ligation. Cytokine 16:1-9, 2001.

6. Jana M, Liu X, Koka S, Ghosh S, Petro TM, and Pahan K. Ligation of CD40 stimulates the induction of nitric oxide synthase in microglial cells. J. Biol. Chem. 276:44527-44533, 2001.

7. Pahan, K., Sheikh, F.G., Liu, X., Hilger, S., McKinney, M.J. and Petro, T.M. Interleukin-12 p40 induced nitric oxide synthase and activates NF-kB in microglial cells. J. Biol. Chem. 276:7899-7905, 2001.

8. Iwasaki, LR, Haack, JE, Nickel, JC, Reinhardt, RA, and Petro, TM. Human interleukin 1-_ and interleukin 1 receptor antagonist secretion and velocity of tooth movement. Archives of Oral Biology 46:185-189, 2001.

9. Jia, W., Beatty, M.W., Reinhardt, R.A., Petro, T.M., Cohen, D.M., Maze, C.R., Strom, E.A., Hoffman, M. Nickel release from orthodontic arch wires and cellular immune response to various nickel concentrations. J. Biomed. Mater. Res. (Appl Biomater) 48:488-495, 1999.

10. Petro, T.M., Schwartzbach, S.D. and Zhang, S. Smokeless tobacco and nicotine bring about excessive cytokine responses of murine memory T cells. J. Immunopharm. 21:103-114, 1999.

11. Petro, TM. ERK-MAP-kinases differentially regulate expression of IL-23 p19 compared with p40 and IFN-beta in Theiler's virus-infected RAW264.7 cells.Immunol Lett. 2005 Feb 15;97(1):47-53.

12. Petro, TM. Disparate expression of IL-12 by SJL/J and B10.S macrophages during Theiler's virus infection is associated with activity of TLR7 and Mitogen-activated Protein Kinases, 2005 In press, Microbes and Infection.

Selected Abstracts:

1. Petro, TM and Zhang, Y, Theiler's virus induction of p35, p40 and p19 IL-12 family subunits is reduced by a p38 MAP-kinase inhibitor.Presented at the American Association of Immunology Annual Meeting, Denver, CO, May 2003

2. Kollet, J, and Petro, TM. In vivo and in vitro interaction of IRF-1 and c-Rel with the proximal Interleukin p35 promtoer. Presented at the American Association of Immunology Annual Meeting, Denver, CO, May 2003

3. Kollet J, Witek C, Gentry JD, Liu X, Schwartzbach SD, and Petro TM. Recruitment of Interferon Regulatory Factor 1 (IRF-1) to the Interleukin-12 recruitment of Interferon Regulatory Factor 1 (IRF-1) to the Interleukin-12 p35 Promoter upon Interferon-[gamma]/LPS Stimulation35 Promoter upon Interferon-_/LPS Stimulation. 41st American Society for Cell Biology Annual Meeting in Washington, DC, December 8-12, 2001.

4. Petro, T.M., Witek, C., Kollet, J., Liu, X., Schwartzbach, S.D. Distinct regulatory elements in the murine IL-12 p35 promoter respond to Interferon-_ and LPS. Presented at the American Association of Immunology Annual Meeting, Seattle, WA, FASEB J 14(6):A1182:#155, April 14, 2000.

5. Petro, T.M., Gentry, J.D., Weatherman, A., Schwartzbach, S.D. Analysis of murine IL-12 p 35 promoter. Experimental Biology, 1999, Washington, D.C., FASEB J 13(5):A651, March 15, 1999.