Catecholamines released from the sympathetic nervous system in response to stress or injury affect expression of inflammatory cytokines generated by immune cells. ␣ 1 -Adrenergic receptors (ARs) are expressed on innate immune cell populations, but their subtype expression patterns and signaling characteristics are not well characterized. Primary human monocytes, a human monocytic cell line, and monocyte-derived macrophage cells were used to measure expression of the proinflammatory mediator interleukin (IL)-1␤ responding to lipopolysaccharide (LPS) in the presence or absence of ␣ 1 -AR activation. Based on our previous findings, we hypothesized that ␣ 1 -AR stimulation on innate immune cells positively regulates LPS-initiated IL-1␤ production. IL-1␤ production in response to LPS was synergistically higher for both monocytes and macrophages in the presence of the selective ␣ 1 -AR agonist (R)-(Ϫ)-phenylephrine hydrochloride (PE). This synergistic IL-1␤ response could be blocked with a selective ␣ 1 -AR antagonist as well as inhibitors of protein kinase C (PKC). Radioligand binding studies characterized a homogenous ␣ 1B -AR subtype population on monocytes, which changed to a heterogeneous receptor subtype expression pattern when differentiated to macrophages. Furthermore, increased p38 mitogenactivated protein kinase (MAPK) activation was observed only with concurrent PE and LPS stimulation, peaking after 120 and 30 min in monocytes and macrophages, respectively. Blocking the PKC/p38 MAPK signaling pathway in both innate immune cell types inhibited the synergistic IL-1␤ increase observed with concurrent PE and LPS treatments. This study characterizes ␣ 1 -AR subtype expression on both human monocyte and macrophage cells and illustrates a mechanism by which increased IL-1␤ production can be modulated by ␣ 1 -AR input.

Numerous lines of evidence point to the tumor promoting properties of prostaglandin (PG)E2. Preclinical studies have demonstrated the ability of both vitamin D (vitD) and celecoxib to downregulate the ecisanoid. We hypothesized that the two agents would work synergistically. The purpose of the study was to determine the dose dependent effects of vitD, with or without celecoxib. 24 women were prospectively enrolled and randomized in double blind fashion for one month (postmenopausal) or one menstrual cycle (premenopausal) to one of four daily treatment regimens: placebo, 400 IU vitD, 2000 IU vitD, or 2000 IU vitD + 400 mg celecoxib. Breast nipple aspirate fluid (NAF) and serum were collected. Both breast specific and systemic levels of PGE2 were measured. There was a significant dose dependent increase in 25(OH)D levels (p<.01). The post-treatment levels of NAF (but not serum) PGE2 were lower and the decrease greater in the 2000 IU vitD than in the other groups (p<.05) of normal risk women. A similar effect was not observed in women at increased breast cancer risk, nor in women receiving vitD + celecoxib. These findings suggest the potential of vitamin D, given in adequate dose, at lowering a key cancer promoting enzyme in women of normal breast cancer risk. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B62.