Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0220723 (PCA)
 4,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In contrast to several inbred strains of mice that develop Th1-associated anticandidal protection, DBA/2 mice are highly susceptible to systemic infection with Candida albicans cells of the attenuated variant PCA-2, and fatal outcome is observed in concurrence with sustained CD4+ cell production in vitro of IL-4 and IL-10. These Th2 cytokines were previously shown to inhibit nitric oxide (NO) production and yeast killing by activated macrophage cultures. We now show that macrophages from DBA/2 mice, either intact or infected with PCA-2, have lower capacity than resistant strains to synthesize NO in response to IFN-gamma. However, when treated with anti-IL-10 Abs at the time of infection, DBA/2 mice survived challenge and displayed increased production of NO in vitro after IFN-gamma activation. Cure was associated with the onset of footpad responses and durable protection, and higher frequencies of IFN-gamma-secreting cells were found in splenic CD4+ lymphocytes that expressed lower levels of IL-4 and IL-10 mRNA. Therefore, in DBA/2 mice, IL-10 contributes significantly to the selection of a Th2 response and lethality after PCA-2 challenge. An IL-10-induced defect in the activation and/or expansion of IFN-gamma-producing Th1 cells, IL-10 suppression of yeast killing, and the relative inability of DBA/2 macrophages to produce adequate levels of candidacidal NO may all contribute to the abnormal susceptibility of these mice to candidiasis.
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PMID:Neutralization of IL-10 up-regulates nitric oxide production and protects susceptible mice from challenge with Candida albicans. 790 4

By means of polymerase chain reaction-assisted mRNA amplification, we have monitored message levels of interleukin (IL)-12 in splenic macrophages and of interferon-gamma (IFN-gamma), IL-4, and IL-10 in CD4+ and CD8+ T cells using Candida albicans/host combinations that result either in a T helper type-1 (Th1)-associated self-limiting infection ("healer mice") or in a Th2-associated progressive disease ("nonhealer mice"). The timing and pattern of message detection did not differ qualitatively by the expression of IFN-gamma or IL-10 mRNA in CD4+ and CD8+ cells from healer (i.e. PCA-2 into CD2F1) vs. nonhealer (i.e. CA-6 into CD2F1 or PCA-2 into DBA/2) mice. In contrast, IL-4 mRNA was uniquely expressed by CD4+ cells from nonhealer animals. IL-12p40 was readily detected in macrophages from healer mice but was detected only early in infection in mice with progressive disease. Cytokine levels were measured in sera, and antigen-driven cytokine production by CD4+ and CD8+ cells was assessed in vitro, while IFN-gamma-producing cells were enumerated in CD4- CD8- cell fractions. Overall, our results showed that (i) antigen-specific secretion of IFN-gamma protein in vitro by CD4+ cells occurred only in healing infection; (ii) IL-4- and IL-10-producing CD4+ cells would expand in nonhealer mice in the face of high levels of circulating IFN-gamma, likely released by CD4- CD8- lymphocytes; (iii) a finely regulated IFN-gamma production correlated in the healer mice with IL-12 mRNA detection, and IL-12 was required in vitro for yeast-induced development of IFN-gamma-producing CD4+ cells. Although the mutually exclusive production of IL-4/IL-10 and IFN-gamma by early CD4+ cells may be the major discriminative factor of cure and noncure responses in candidiasis, IL-12 rather than IFN-gamma production may be an indicator of Th1 differentiation.
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PMID:Interleukin-12 but not interferon-gamma production correlates with induction of T helper type-1 phenotype in murine candidiasis. 790 34

We have previously demonstrated that the hyphal form of Candida albicans (H-Candida), but not the yeast form (Y-Candida), acts as a macrophage-stimulating agent. The early response (1 to 3 h) of the macrophage cell line ANA-1 to H-Candida results in enhanced tumor necrosis factor (TNF) transcription and production. Here we show that when coincubation times are prolonged (3 to 24 h), Y-Candida also exhibits stimulatory properties. This phenomenon has been ascribed to the occurrence of the dimorphic transition, as demonstrated by microscopic evaluation of the cultures and by experiments in which both killed Y-Candida and the agerminative strain C. albicans PCA-2 failed to induce cytokine production. TNF produced in response to H-Candida acts as an autocrine and paracrine signal controlling the macrophage secretory response to C. albicans. In fact, addition of anti-TNF polyclonal antibodies to the coculture of ANA-1 macrophages and H-Candida results in a marked and time-dependent decrease of TNF transcript levels. Moreover, pretreatment of macrophages with recombinant TNF for 3 h enhances TNF and induces interleukin-1 production in response to both forms of Candida, while pretreatment for 18 h renders macrophages refractory to any stimuli. Interestingly, the kinetics of interleukin-1 transcription and secretion in response to H-Candida are delayed with respect to those of TNF. Overall, these data indicate that TNF, produced by macrophages in response to H-Candida, regulates its own production as well as that of other soluble factors, thus suggesting that this cytokine plays multiple roles in the immune mechanisms involved in Candida infection.
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PMID:Tumor necrosis factor as an autocrine and paracrine signal controlling the macrophage secretory response to Candida albicans. 813 26