Publications by authors named "Luis Caveda"

3 Publications

  • Page 1 of 1

Tumor cells deactivate human monocytes by up-regulating IL-1 receptor associated kinase-M expression via CD44 and TLR4.

J Immunol 2005 Mar;174(5):3032-40

Research Unit, Department of Surgical Research, La Paz Hospital, Madrid, Spain.

Although blood monocytes possess significant cytotoxic activity against tumor cells, tumor-infiltrating monocytes are commonly deactivated in cancer patients. Monocytes pre-exposed to tumor cells show significantly decreased expression levels of TNF-alpha, IL-12p40, and IL-1R-associated kinase (IRAK)-1. Activation of the Ser/Thr kinase IRAK-1 is an important event in several inflammatory processes. By contrast, another IRAK family member, IRAK-M, negatively regulates this pathway, and is up-regulated in cultures of endotoxin-tolerant monocytes and in monocytes from septic patients within the timeframe of tolerance. In this study, we show that IRAK-M expression is enhanced at the mRNA and protein level in human monocytes cultured in the presence of tumor cells. IRAK-M was induced in monocytes upon coculturing with different tumor cells, as well as by fixed tumor cells and medium supplemented with the supernatant from tumor cell cultures. Moreover, blood monocytes from patients with chronic myeloid leukemia and patients with metastasis also overexpressed IRAK-M. Low concentrations of hyaluronan, a cell surface glycosaminoglycan released by tumor cells, also up-regulated IRAK-M. The induction of IRAK-M by hyaluronan and tumor cells was abolished by incubation with anti-CD44 or anti-TLR4 blocking Abs. Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-alpha mRNA expression and protein production in human monocytes re-exposed to a tumor cell line. Altogether, our findings indicate that deactivation of human monocytes in the presence of tumor cells involves IRAK-M up-regulation, and this effect appears to be mediated by hyaluronan through the engagement of CD44 and TLR4.
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http://dx.doi.org/10.4049/jimmunol.174.5.3032DOI Listing
March 2005

Nitric oxide activates the expression of IRAK-M via the release of TNF-alpha in human monocytes.

Nitric Oxide 2004 Jun;10(4):213-20

Research Unit, Department of Surgical Research, La Paz Hospital, Madrid 28046, Spain.

The activation of interleukin receptor associated kinases (IRAK) is an important event in several inflammatory processes. However, exposing monocytes to a nitric oxide (NO) donor inhibits the activity of IRAK-1 and its molecular interaction with TNF receptor associated factor-6 (TRAF6). Despite the fact that NO is known to regulate many events in the immune and vascular system, the mechanism that underlies this inhibition remains unknown. We have recently demonstrated that IRAK-M inhibits the TLR/IRAK pathway during endotoxin tolerance and thus, we hypothesized that IRAK-M may be involved in the inhibition of IRAK-1 activity in the presence of NO. Hence, we have analyzed the expression of IRAK-M in human monocytes following exposure to a NO donor (GSNO) and we have observed that GSNO was capable of inducing IRAK-M mRNA and protein expression 8 and 20 h after stimulation, respectively. It is known that NO induces the expression of TNF-alpha in monocytes and we found that exposure to TNF-alpha induced IRAK-M mRNA expression in human monocytes within 2 h of stimulation. Furthermore, the expression of IRAK-M induced by GSNO was inhibited by the presence of a blocking antibody raised against TNF-alpha. Thus, our data indicate that stimulation of human monocytes with a NO donor results in a clear induction of IRAK-M and this is dependent on the release of TNF-alpha by this kind of cells.
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http://dx.doi.org/10.1016/j.niox.2004.04.007DOI Listing
June 2004

Hepatocyte growth factor activates endothelial proangiogenic mechanisms relevant in chronic hepatitis C-associated neoangiogenesis.

J Hepatol 2003 May;38(5):660-7

Liver Unit (planta 3), Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Diego de León 62, E-28006 Madrid, Spain.

Background: Angiogenesis occurs in inflamed portal tracts of chronic hepatitis C (CHC) patients.

Aims: To characterize this phenomenon, by investigating the molecular mechanisms involved in neovessel formation in the livers of CHC patients and the angiogenic effects of hepatocyte growth factor (HGF) on human endothelial cells.

Methods: Vascular endothelial growth factor (VEGF), VE-cadherin and alphavbeta3 integrin were determined in CHC biopsies by Western blot and immunohistochemistry. Effects of HGF on VEGF and cell adhesion molecules expression by cultured human microvascular endothelial cells were evaluated by Western blot, Northern blot or immunofluorescence. HGF effects on cell proliferation were assessed by [(3)H]thymidine incorporation.

Results: VEGF, VE-cadherin and alphavbeta3 integrin were increased in CHC liver samples. In cultured endothelial cells, HGF transcriptionally increased VEGF expression, an effect which was blocked by an anti-VEGF receptor antibody. HGF transiently decreased VE-cadherin expression and its associated cytoskeleton-linking molecule beta-catenin, thus weakening intercellular contacts. HGF increased alphavbeta3 integrin at focal contacts, and cell proliferation, an effect which was inhibited by an anti-VEGF receptor antibody.

Conclusions: Our results show that HGF and VEGF modulate the expression of cell adhesion and migration molecules and induce proliferation in endothelial cells, mechanisms through which these factors may contribute to CHC-associated liver angiogenesis.
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http://dx.doi.org/10.1016/s0168-8278(03)00053-9DOI Listing
May 2003
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