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Infection and Immunity, May 2004, p. 2513-2520, Vol. 72, No. 5
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.5.2513-2520.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Monocytic Interleukin-12 Production by Candida albicans via Selective Activation of ERK Mitogen-Activated Protein Kinase

Ningfeng Tang,^1,2, Liming Liu,^1,2, Kefei Kang,^1,2* Pranab K. Mukherjee,^1,2 Masakazu Takahara,^1,3 Guofen Chen,¹ Thomas S. McCormick,¹ Kevin D. Cooper,^1,4 and Mahmoud Ghannoum^1,2,4

Department of Dermatology,¹ Center for Medical Mycology, University Hospitals of Cleveland, Case Western Reserve University,² Veteran Affairs Medical Center, Cleveland, Ohio,⁴ Department of Dermatology, Kyushu University, Fukuoka, Japan³

Received 29 October 2003/ Returned for modification 22 December 2003/ Accepted 3 February 2004

Our previous data demonstrated that live Candida albicans inhibits interleukin-12 (IL-12) production by human monocytes. Here we explored whether C. albicans inhibits IL-12 via a released factor and whether the inhibition is mediated via mitogen-activated protein kinase (MAPK) regulation. Supernatant fluids were obtained from cultured C. albicans (SC5314) as well as cultured Saccharomyces cerevisiae after 20 h of incubation. At 2 h postincubation of monocytes with heat-killed C. albicans (HKCA) (2:1) to stimulate IL-12, concentrated fungal supernatant fluids were added and incubated for an additional 20 h. The present data show that, unlike supernatant fluids obtained from S. cerevisiae, the C. albicans supernatant fluids significantly suppressed IL-12 production induced by HKCA. This suggested that the inhibition is Candida specific. A preliminary biochemical analysis revealed that this secretory IL-12 inhibitory factor is glycoprotein in nature. The inhibitory activity had no effect on the phagocytosis of yeasts. Supernatant fluids from C. albicans markedly induced the phosphorylation of ERK44/42 MAPK, but not p38 and SAPK, 1 min after they were added to monocytes. To test if the induction of ERK44/42 MAPK was central to the IL-12 inhibition, we used gamma interferon (IFN-) (1 ng/ml) plus lipopolysaccharide (LPS) (100 ng/ml) to stimulate IL-12 production by monocytes. The inhibition of ERK MAPK by the specific inhibitor PD 98059 significantly reduced phospho-ERK44/42 MAPK levels induced by C. albicans supernatant fluids in the IFN--plus-LPS-driven monocytes. Concomitantly, PD 98059 reversed the IL-12 inhibitory activity of the C. albicans supernatant (P < 0.01). These data indicate that C. albicans can inhibit IL-12 production by secreting an ERK44/42 MAPK-stimulating factor and thus can attenuate effective immune responses.

Editor: T. R. Kozel

N.T. and L.L. contributed equally to the paper.

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