4-Hydroxynonenal Decreases Interleukin-6 Expression and Protein Production in Primary Rat Kupffer Cells by Inhibiting Nuclear Factor-κB Activation

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Abstract
Zinc porphyrins have anti-inflammatory and anti-allergic properties. The objective of the present study was to characterize the mechanism of zinc tetrakis-(N-methyl-4′-pyridyl) porphyrinato (ZnTMPyP) immune modulation by investigating its effects on the proliferative activity during thymocyte stimulation with mitogenic factors and the molecular events mediating thymocyte proliferation. The results indicate that ZnTMPyP inhibited thymocyte proliferation stimulated with various mitogenic factors, such as concanavalin A (Con A), interleukin (IL)-1β, and lipopolysaccharide-exposed macrophage supernatant, in a concentration-dependent manner. ZnTMPyP was also effective in preventing DNA binding activity of nuclear factor κB (NF-κB) and IL-2 production by thymocytes in response to Con A or IL-1β. Inhibition of p38 mitogen-activated protein kinase (MAPK) with SB203580 substantially inhibited Con A- or IL-1β-induced DNA binding activity of NF-κB, whereas ZnTMPyP inhibited the activation of p38 MAPK. ZnTMPyP also inhibited Con A-induced chemiluminescence and tyrosine phosphorylation by thymocytes. In conclusion, our findings suggest that the antiproliferative effect of ZnTMPyP may be mediated by effective inhibition of the production of reactive oxygen species, tyrosine phosphorylation, p38 MAPK activation, NF-κB activation, and IL-2 production during mitogenic stimulation of thymocytes.