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HYPOXIA INDUCES INTERLEUKIN-1-BETA EXPRESSION IN RAT MONOCYTES INVOLVING IN PKC/RAF-1/MAPK/NF-B PATHWAY

Xinqiao Hospital, Third Military Medical University, Chongqing, Peoples Rep of China

PURPOSE: The objective of this paper is to determine whether hypoxia induces interleukin-1 beta (IL-1ß) expression of rat monocytes involving in PKC/Raf-1/ MAPK/NF-B pathway.

METHODS: Rat monocytes were subjected to 0, 1, 3, 6, 9, 12 and 24 h of hypoxia (3%O2, 5%CO2, 82%N2) with or without isoform-selective PKC inhibitors, Raf-1 inhibitor, MAPK inhibitor and NF-B inhibitor respectively. PKC and Raf-1 activity were analyzed by PKC kit and Raf-1 kinase cascade assay kit. NF-B binding activity was analyzed by electrophoretic mobility shift assay. IL-1ß mRNA levels were determined by reverse transcription-polymerase chain reaction.

RESULTS: Hypoxia induced significantly IL-1ß mRNA expression (p ?? 0.01-0.05) in rat monocytes by increased activities of PKC, Raf-1, MAPK and NF-B. PKC inhibitor, Safingol, blocked hypoxia-mediated IL-1ß mRNA expression and the inhibitors of other PKC isoforms had no effect. The results suggest that only PKC play a role in induction of IL-1ß expression by hypoxia. In addition, it was the Raf-1 inhibitor, GW 5074, rather than Ras inhibitor, manumycin A, suppressed hypoxia-mediated IL-1ß mRNA expression, indicating that the induction of IL-1ß mRNA expression by hypoxia depends on Raf-1, but not Ras. Moreover, the MAPK and NF-B inhibitors decreased hypoxia-mediated IL-1ß mRNA expression. It confirms the critical roles of MAPK and NF-B in IL-1ß induction in rat monocytes exposed to hypoxia.

CONCLUSION: Taken together, these data suggest that hypoxia induces significantly IL-1ß expression in rat monocytes involving in the coordinate activity of PKC/Raf-1/MAPK/NF-B signaling pathway.

CLINICAL IMPLICATIONS: Although further studies are required to precisely define the potential functional role of hypoxia-mediated IL-1ß expression in ARDS, our studies contribute to an understanding of signal transduction during the activation of rat monocytes and releasing IL-1ß by hypoxia. Data accumulating via connected studies should be helpful in the development of therapeutic methods for ARDS and MODS.

DISCLOSURE: Guoming Wu, None.