The production in colon cancer of interferon-gamma (IFN-gamma), a type-1 T-helper (TH1) cytokine, is considered as a marker of good prognosis. We asked whether interleukin-18 (IL-18), which strongly induces IFN-gamma and regulates Fas ligand (Fas-L)-dependent cytotoxicity, may play a role in colon homeostasis, and if its expression was modulated in colon adenocarcinomas. We analyzed 14 specimens of colon adenocarcinomas, 6 of normal colon mucosa of the series, and 6 colon-tumor cell lines. The expression of IL-18, of ICE protease, involved in the processing of this cytokine, and of the downstream effectors of IL-18, IFN-gamma and Fas-L was analyzed by RT-PCR. We further performed IL-18 immunostaining of normal and tumor specimens. The results were correlated with tumor dissemination and clinical outcome. We report the synthesis of IL-18 in human normal colon, mainly by epithelial cells of the mucosa. Out of the 6 tumor cell lines, 4 expressed IL-18 transcripts, but neither ICE mRNA nor secreted forms of IL-18 were detected. We observed decreased or abolished synthesis of IL-18 in colon adenocarcinomas, as compared with normal mucosa. Thus, half of the colon-cancer tissues (7/14 cases) expressed neither IFN-gamma nor Fas-L. This feature was correlated with the existence of distant metastases (Fischer's exact test, p = 0.02) and an unfavorable outcome. These findings suggest that production of IL-18 in human colon may play a role in homeostasis and in tumor immune surveillance, by enhancing IFN-gamma production and Fas-L-dependent cytotoxicity of immune cells.

Caspase 1↗

PubMed1999

Neural stem cells successfully transplanted

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Journal Article↗

PubMed1999

Gonads are the key to a long life

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Journal Article↗

PubMed1999

High dose chemotherapy offers little benefit in breast cancer.

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Antineoplastic Agents↗

PubMed1999

Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy.

OBJECTIVE: HIV-induced CD4 lymphocyte depletion is partially reversed by antiretroviral therapy but it is unclear if the degree to which the CD4 count rises depends on viral suppression (if so, the extent of viral suppression required to achieve a maximal CD4 count rise), whether the rise is sustainable and whether it occurs in patients with CD4 count <10 x 10(6) cells/l. We aimed to address these issues. METHODS: We studied CD4 count and plasma HIV RNA values every 4 weeks for 72 weeks in 154 patients starting indinavir-containing regimens. RESULTS: Mean baseline HIV RNA and CD4 count were 4.8 log10 copies/ml and 180 x 10(6) cells/l, respectively. Overall, there was a mean increase in CD4 count of 143 x 10(6) cells/l by 72 weeks. The adjusted mean increase (adjusted for initial viral load, CD4 count and age) was strongly related to the mean viral suppression over the follow-up period (P < 0.0001). Importantly, there was a highly significant difference (P = 0.0004) in the rise in CD4 count between those with 2-3 log suppression (161 x 10(6) cells/l) and those with > 3 log suppression (314 x 10(6) cells/l; mean 3.6 log suppression in this group), suggesting that with even greater suppression the rise in CD4 lymphocytes may be still larger. We also studied whether CD4 counts were still rising after 72 weeks in patients with sustained suppression of at least 3 log in viral load. There was a significant (P = 0.004; paired t-test) rise in count of 43 x 10(6) cells/l between weeks 64 and 72 in these patients, suggesting that regeneration continues at least up to 72 weeks after therapy, provided virus replication continues to be suppressed. Patients with initial CD4 counts < 10 x 10(6) cells/l experienced no smaller rises than those at higher levels, even after adjustment for other factors. CONCLUSION: These results strongly support a direct causal relationship between HIV replication and CD4 lymphocyte count depletion. The rise in those with > 3 log suppression provides the best available indicator of the potential for natural CD4 regeneration in HIV-infected patients. However, since still greater CD4 count rises may be seen with more suppressive regimens, it may not be possible to study the intrinsic CD4 regenerative capacity until such regimens are available.

Adult↗

PubMed1999

The Painter's Eye

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Journal Article↗

PubMed1999

Control of tumor development by intratumoral cytokines.

The local immune reactions may influence the clinical outcome of human tumors. In carcinoma of the cervix, high gene expression of IL6 with tumor invasiveness whereas lack of gene expression of IFNbeta is correlated with poor prognosis. In colorectal cancer, lack of expression of IFNbeta is associated with the presence of distant metastasis and poor survival. The production of IL17 and IL18, inducers of IL6 and IFNbeta respectively is regulated in these tumors and may control the levels of the effector cytokines, i.e. IL6 and IFNbeta. The mechanisms by which these cytokines act are linked to the recruitment of effector cells such as macrophages.

Animals↗

PubMed1999