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The Journal of Immunology, 2001, 166: 4620-4626.
Copyright © 2001 by The American Association of Immunologists

Toll-Like Receptor 4 Mediates Intracellular Signaling Without TNF-{alpha} Release in Response to Cryptococcus neoformans Polysaccharide Capsule1

Shmuel Shoham, Chao Huang, Jian-Min Chen, Douglas T. Golenbock and Stuart M. Levitz2

The Evans Memorial Department of Clinical Research and Department of Medicine, Boston University School of Medicine, Boston, MA 02118

Toll-like receptors (TLR) 2 and 4 are cell surface receptors that in association with CD14 enable phagocytic inflammatory responses to a variety of microbial products. Activation via these receptors triggers signaling cascades, resulting in nuclear translocation of NF-{kappa}B and a proinflammatory response including TNF-{alpha} production. We investigated whether TLRs participate in the host response to Cryptococcus neoformans glucuronoxylomannan (GXM), the major capsular polysaccharide of this fungus. Chinese hamster ovary fibroblasts transfected with human TLR2, TLR4, and/or CD14 bound fluorescently labeled GXM. The transfected Chinese hamster ovary cells were challenged with GXM, and activation of an NF-{kappa}B-dependent reporter construct was evaluated. Activation was observed in cells transfected with both CD14 and TLR4. GXM also stimulated nuclear NF-{kappa}B translocation in PBMC and RAW 264.7 cells. However, stimulation of these cells with GXM resulted in neither TNF-{alpha} secretion nor activation of the extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun N-terminal kinase mitogen-activated protein kinase pathways. These findings suggest that TLRs, in conjunction with CD14, function as pattern recognition receptors for GXM. Furthermore, whereas GXM stimulates cells to translocate NF-{kappa}B to the nucleus, it does not induce activation of mitogen-activated protein kinase pathways or release of TNF-{alpha}. Taken together, these observations suggest a novel scenario whereby GXM stimulates cells via CD14 and TLR4, resulting in an incomplete activation of pathways necessary for TNF-{alpha} production.




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