In mammals, tissue damage or infection leads to a cytokine induced reorchestration of gene expression in the liver resulting in a change in the concentration of a group of serum proteins called the acute phase reactants. The focus of the work in the Samols lab is to understand the dramatic change in abundance of the prototypic acute phase protein, C-reactive protein (CRP) as well as its in vivo function. CRP is a very sensitive reflector of inflammatory status. It is associated with innate immunity and is presumed to play an important role in host defense systems. CRP expression is regulated by cytokines IL-6 and IL-1 through the participation of transcription factors C/EBP, STAT3 and NFκB (rel proteins). Our studies focus on the unique combinations of interactions on the promoter. We have found that the binding of C/EBPβ is critical for cytokine responsiveness and that rel proteins participate in an indirect manner to synergistically activate the transcriptional process. In a separate project, we focus on the function of CRP. Based on in vitro studies, three hallmark properties of CRP have been described; 1) its ability to bind phosphocholine-containing compounds, 2) its ability to bind C1q and activate the classical complement cascade and 3) its ability to interact with IgG receptors on leukocytes. We have created transgenic mice that express CRP driven by a PEPCK promoter in an attempt to determine if these in vitro properties are important in vivo. We have used these mice in three inflammatory models: a model of systemic inflammation employing mediators of septic shock, a model of local inflammation employing pulmonary alveolitis induced with chemokines, and a model of immune-mediated inflammation employing antigen-induced arthritis. In all three, CRP had marked anti-inflammatory properties.
- Kushner I., Samols D., and Magrey M.
“A unifying biologic explanation for "high-sensitivity" C-reactive protein and "low-grade" inflammation”
Arthritis Care Res (Hoboken) 62 (4): 442-6 (2010).
- Gaitonde S., Samols D., and Kushner I.
“C-reactive protein and systemic lupus erythematosus”
Arthritis Rheum 59 (12): 1814-20 (2008).
- Young D. P., Kushner I., and Samols D.
“Binding of C/EBPbeta to the C-reactive protein (CRP) promoter in Hep3B cells is associated with transcription of CRP mRNA”
J Immunol 181 (4): 2420-7 (2008).
- Jiang S., Xia D., and Samols D.
“Expression of rabbit C-reactive protein in transgenic mice inhibits development of antigen-induced arthritis”
Scand J Rheumatol 35 (5): 351-5 (2006).
- Kushner, I, D. Rzewnicki and D. Samols
“What does minor elevation of C-reactive protein signify”
Am J. Med. 119, 166.e17-166.e28. (2006)
- Black S., Kushner I., and Samols D.
J Biol Chem 279 (47): 48487-90 (2004).
- Samols, D., A. Agrawal and I. Kushner
“Acute Phase Proteins (2002)”
In: Oppenheim, J. J. and Feldman, M. (Eds.). Cytokine Reference On-Line
Academic Press, Harcourt, London, UK, Website: www.academicpress.com/cytokinereference