The commensal fungus Candida albicans causes oropharyngeal candidiasis (OPC; thrush) in settings of immunodeficiency. Although disseminated, vaginal, and oral candidiasis are all caused by C. albicans species, host defense against C. albicans varies by anatomical location. T helper 1 (Th1) cells have long been implicated in defense against candidiasis, whereas the role of Th17 cells remains controversial. IL-17 mediates inflammatory pathology in a gastric model of mucosal candidiasis, but is host protective in disseminated disease. Here, we directly compared Th1 and Th17 function in a model of OPC. Th17-deficient (IL-23p19−/−) and IL-17R–deficient (IL-17RA−/−) mice experienced severe OPC, whereas Th1-deficient (IL-12p35−/−) mice showed low fungal burdens and no overt disease. Neutrophil recruitment was impaired in IL-23p19−/− and IL-17RA−/−, but not IL-12−/−, mice, and TCR-αβ cells were more important than TCR-γδ cells. Surprisingly, mice deficient in the Th17 cytokine IL-22 were only mildly susceptible to OPC, indicating that IL-17 rather than IL-22 is vital in defense against oral candidiasis. Gene profiling of oral mucosal tissue showed strong induction of Th17 signature genes, including CXC chemokines and β defensin-3. Saliva from Th17-deficient, but not Th1-deficient, mice exhibited reduced candidacidal activity. Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors.

Anoxia, glucose starvation, calcium ionophore A23187, EDTA, glucosamine, and several other conditions that adversely affect the function of the endoplasmic reticulum (ER) induce the synthesis of the glucose-regulated class of stress proteins (GRPs). The primary GRPs induced by these stresses migrate at 78 and 94 kDa (GRP78 and GRP94). In addition, another protein of -150-170 kDa (GRP170) has been previously observed and is coordinately induced with GRP78 and GRP94. To characterize this novel stress protein, we have prepared an antisera against purified GRP170. Immunofluorescence, Endoglycosidase H sensitivity, and protease resistance of this protein in microsomes indicates that GRP1 70 is an ER lumenal glycoprotein retained in a pre-Golgi compartment. Immunoprecipitation of GRP170 with our antibody coprecipitates the GRP78 (also referred to as the B cell immunoglobulin-binding protein) and GRP94 members of this stress protein family in Chinese hamster ovary cells under stress conditions. ATP depletion, by immunoprecipitation in the presence of apyrase, does not affect the interaction between GRP78 and GRP170 but results in the coprecipitation of an unidentified 60-kDa protein. In addition, GRP170 is found to be coprecipitated with immunoglobulin (Ig) in four different B cell hybridomas expressing surface IgM, cytoplasmic Ig light chain only, cytoplasmic Ig heavy chain only, or an antigen specific secreted IgG. In addition, in IgM surface expressing WEHI-231 B cells, anti-IgM coprecipitates GRP78, GRP94, as well as GRP170; antibodies against GRP170 and GRP94 reciprocally coprecipitate GRP94/GRP170 as well as GRP78. Results suggest that this 170-kDa GRP is a retained ER lumenal glycoprotein that is constitutively present and that may play a role in immunoglobulin folding and assembly in conjunction or consecutively with GRP78 and GRP94. INTRODUCTIONThe heat shock proteins or stress proteins are a set of

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Conjugated linoleic acid (CLA), a family of isomers of octadecadienoic acid, inhibits rat mammary carcinogenesis, angiogenesis, and lung metastasis from a transplantable mammary tumor. c9,t11-CLA, the predominant isomer in dairy products, and t10,c12-CLA, a component of CLA supplements, are equally effective. The objective of the current studies was to test the efficacy of these two CLA isomers in a clinically relevant breast cancer model. Transgenic mice over-expressing erbB2 in the mammary epithelium were fed control or 0.5% CLA-supplemented diets continuously from weaning. Unexpectedly, t10,c12-CLA stimulated lobular hyperplasia of the mammary epithelium and accelerated mammary tumor development, decreasing median tumor latency to 168 days of age compared with 256 and 270 days in the c9,t11-CLA and control groups, respectively. Metastasis was also increased by t10,c12-CLA, with percentage of tumor-bearing mice with lung metastasis 73, 14 and 31% in the t10,c12-CLA, c9,t11-CLA and control groups, respectively. A second study, in which CLA administration was initiated after puberty, confirmed the stimulatory effect of t10,c12-CLA on mammary tumor development and metastasis. Additionally, t10,c12-CLA, but not c9,t11-CLA, increased the size of the liver, heart, spleen and mammary lymph node. The effects of t10,c12-CLA were not specific to erbB2 transgenic mice, as t10,c12-CLA supplementation increased proliferation in the mammary epithelium of both wild-type FVB and FVB/erbB2 mice. Moreover, the number of terminal end buds, the mammary epithelial structures most sensitive to a carcinogenic insult, was increased 30-fold in FVB wild-type mice fed t10,c12-CLA. These data suggest that it would be prudent to avoid CLA supplements containing the t10,c12-CLA isomer. However, even though c9,t11-CLA was not efficacious in the erbB2 model, its ability to inhibit mammary tumor development in rat models suggests that it may have activity for prevention of some types of breast cancer.