This may explain the discrepancy between our findings and the previous report demonstrating reduced Loreclezole hydrochloride atherogenesis by mepyramine or H1R deletion in ApoE2/2 mice. Also, unique chemical and pharmacological properties of these different H1-antihistamines secondary to antagonizing H1R signaling may result in their adverse outcomes. A second possibility is that high doses of these H1-antihistamines switch H1R into an inactive conformation because of their inverse agonistic properties. The molecular basis of the mode of action of second generation antihistamines demonstrates unique LP 12 hydrochloride receptor binding characteristics, since they bind to H1R as inverse agonists rather than antagonists. Since cetirizine and fexofenadine are inverse H1R agonists, they can generate opposite pharmacological effects compared to the agonist. Thus, in the absence of agonist binding, an inverse agonist can induce overwhelming negative impacts, especially under in vivo conditions with chronic blockade of the receptor signaling. It is possible that higher doses of inverse agonists may irreversibly modulate the receptor signaling or promiscuously bind to other histamine receptors such as H4R. This may explain the results of increased atherogenic effects of cetirizine and fexofenadine at the low doses, and not at the high doses. Atherogenesis involves increased recruitment of macrophages, T lymphocytes and mast cells in a lesion. Macrophages are critical in atherogenic initiation as they transform to foam cells. It has been reported that the T lymphocyte deficiency reduces lesion formation during moderate hypercholesterolemia. Increased number of mast cells are known to be present in the adventitia of atherosclerotic lesions. In the present study, the increase in lesion formation by low doses of cetirizine or fexofenadine was not associated with an increased macrophage or T lymphocyte count. High doses of these H1-antihistamines, on the other hand, were found to reduce the macrophage content without changing the T lymphocytes. Low dose of cetirizine or fexofenadine reduced mast cell recruitment into the plaque area although the effect of cetirizine was not statistically significant. This is opposite to the contention that mast cells promote atherogenesis. This reduction in mast cell numbers in the plaque might be due to increased degranulation. The amount of scavenger receptor CD36 was also found not to be affected by low doses of H1- antihistamines. Cytokines and chemokines derived from activated mast cells, macrophages and other cell types have unique effects in propagating proinflammatory and atherogenic signals. This study provides insight into the alterations in serum cytokine and chemokine levels in ApoE2/2 mice treated with H1-antihistamines. In the present study, concentrations of various proatherogenic cytokines are altered by low dose of cetirizine or fexofenadine. Proatherogenic cytokines such as IL-1a and MIP-3 levels are reduced in fexofenadine or cetirizine-treated mice, respectively. In contrast, MIP-1a was increased in fexofenadine treated mice.