Protein–1 via Toll-Like Receptor 2 in Macrophages

We examined the role of Toll-like receptors (TLRs) by using TLR2-deficient (TLR2/), TLR4-defective (TLR4d/d), and double-knockout murine macrophages and human embryonic kidney (HEK) 293 cells transfected with human TLR2 or TLR4 expression plasmids after stimulation with different preparations of the human path-ogenic fungus Candida albicans. Compared with wild-type macrophages, TLR2/ and TLR4d/d macrophages had impaired recognition of viable C. albicans, whereas antimycotic (AM)–treated C. albicans solely used TLR2 in a TLR4- and interferon-g–independent manner. In human HEK293 cells, AM-treated C. albicans elicited mainly TLR2-dependent activation. The differences in responsiveness to viable C. albicans, compared with C. albicans treated with cytoplasmic membrane–interacting AMs, suggest specific recognition of different path-ogen-associated patterns by TLRs in innate antifungal responses. Our analyses of signal transduction after stimulation of wild-type macrophages with AM-treated C. albicans demonstrated involvement of the tran-scription factors nuclear factor–kB and c-Jun/activator protein–1 and of the mitogen-activated protein kinases p38, extracellular-related kinase, and c-Jun NH2-terminal kinase. The polymorphic yeast Candida albicans is a pathogenic fungus with increasing medical importance. In patients who are immunosuppressed because of chemotherap