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Published online before print February 8, 2007

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(Journal of Leukocyte Biology. 2007;81:1322-1332.)
© 2007 by Society for Leukocyte Biology

Hydrogen sulfide induces the synthesis of proinflammatory cytokines in human monocyte cell line U937 via the ERK-NF-B pathway

Department of Pharmacology, National University of Singapore, Singapore

¹ Correspondence: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Life Sciences, 28 Medical Drive, Singapore 117456. E-mail: mbhatia{at}nus.edu.sg

Hydrogen sulfide (H₂S) is now considered an endogenous, gaseous mediator, which has been demonstrated to be involved in many inflammatory states. However, the mechanism of its proinflammatory function remains unknown. In the present study, we used IFN--primed human monocytic cell line U937 to investigate the effects of H₂S in vitro on monocytes. We found that treatment with the H₂S donor, sodium hydrosulfide, led to significant increases in the mRNA expression and protein production of TNF-, IL-1ß, and IL-6 in U937 cells. H₂S-triggered monocyte activation was confirmed further by the up-regulation of CD11b expression on the cell surface. We also observed that H₂S could induce a rapid degradation of IB and subsequent activation of NF-B p65, and this effect was attenuated by Bay 11-7082, a specific inhibitor of NF-B. Furthermore, pretreatment of cells with Bay 11-7082 substantially inhibited the secretion of TNF-, IL-1ß, and IL-6 induced by H₂S. We also found that H₂S stimulated the phosphorylation and activation of ERK1/2, but not of p38 MAPK and JNK, and pretreatment with PD98059, a selective MEK1 antagonist, could inhibit H₂S-induced NF-B activation markedly. Together, our findings suggest for the first time that H₂S stimulates the activation of human monocytes with the generation of proinflammatory cytokines, and this response is, at least partially, through the ERK-NF-B signaling pathway.

Key Words: H₂S • inflammation • leukocyte • transcription factor • MAPK

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