Our long-range goal is to identify and characterize genes through which steroidal hormones affect the onset and/or severity of human disease. The objective of this application is to determine a gene in macrophages affected by estrogen withdrawal, as seen post-partum and at menopause, that functions in immune processes. Our central hypothesis is that changes in estrogen concentrations directly regulate IgG Fc gamma receptor III-A (CD16a) expression resulting in a modulation of pro-inflammatory cytokine production and/or release from macrophages upon receptor binding. This hypothesis is based on our recent findings in vitro that 1) the level of Fc gamma RIIIA transcript increased in macrophage-like THP-1 cells and in primary, peripheral blood macrophages after estrogen removal and 2) that the observed increase was dependent on transcription. The hypothesis also includes data from another lab that binding of Fc gamma RIIIA by anti-Fc gamma RIll monoclonal antibodies stimulates macrophage TNF-alpha and IL-1 alpha release. Fc gamma RIIIA is a receptor that selectively binds IgG molecules, an important rheumatoid factor (RF) in auto-immune disease. Collectively, these data suggest that RF binding of this receptor stimulates cytokine release in rheumatoid arthritis and associated temporomandibular joint disorders (TMJD). To test our central hypothesis aim one will characterize macrophage cytokine production and release from stimulated macrophages after modulating Fc gamma RIIIA expression. TNF-alpha and IL-1 alpha will be measured after changing Fc gamma RIIIA expression levels using various estrogen and Fc gamma RIIIA antisense treatments.
Aim two will focus on the mechanism inducing cytokine production and/or release upon Fc gamma RIIIA crosslinking. Signal transduction pathways and activated transcription factors will be identified as well as regulatory TNF-alpha and IL-1 alpha promoter sequences.
Aim three will address the mechanism by which estrogen regulates Fc gamma RIIIA gene transcription in macrophages. The function of estrogen receptors ER alpha and/or ER beta will be directly addressed pharmacologically (e.g., antiestrogen) and through mutation studies of the Fc gamma RIIIA promoter.
|Kramer, P R; Bellinger, L L (2014) Infusion of Gabr?6 siRNA into the trigeminal ganglia increased the myogenic orofacial nociceptive response of ovariectomized rats treated with 17?-estradiol. Neuroscience 278:144-53|
|Kramer, P R; Bellinger, L L (2013) Modulation of temporomandibular joint nociception and inflammation in male rats after administering a physiological concentration of 17?-oestradiol. Eur J Pain 17:174-84|
|Kramer, P R; He, J; Puri, J et al. (2012) A non-invasive model for measuring nociception after tooth pulp exposure. J Dent Res 91:883-7|
|Puri, J; Vinothini, P; Reuben, J et al. (2012) Reduced GABA(A) receptor ?6 expression in the trigeminal ganglion alters inflammatory TMJ hypersensitivity. Neuroscience 213:179-90|
|Puri, Jyoti; Bellinger, Larry L; Kramer, Phillip R (2011) Estrogen in cycling rats alters gene expression in the temporomandibular joint, trigeminal ganglia and trigeminal subnucleus caudalis/upper cervical cord junction. J Cell Physiol 226:3169-80|
|Kramer, Phillip R; Kerins, Carolyn A; Schneiderman, Emet et al. (2010) Measuring persistent temporomandibular joint nociception in rats and two mice strains. Physiol Behav 99:669-78|
|Kramer, Phillip R; Puri, Jyoti; Bellinger, Larry L (2010) Knockdown of Fc? receptor III in an arthritic temporomandibular joint reduces the nociceptive response in rats. Arthritis Rheum 62:3109-18|
|Kramer, Phillip R; Winger, Vanessa; Reuben, Jayne (2009) PI3K limits TNF-alpha production in CD16-activated monocytes. Eur J Immunol 39:561-70|
|Puri, Jyoti; Hutchins, Bob; Bellinger, Larry L et al. (2009) Estrogen and inflammation modulate estrogen receptor alpha expression in specific tissues of the temporomandibular joint. Reprod Biol Endocrinol 7:155|
|Kramer, Phillip R; Janikkeith, Andrea; Cai, Zhuo et al. (2009) Integrin mediated attachment of periodontal ligament to titanium surfaces. Dent Mater 25:877-83|
Showing the most recent 10 out of 16 publications