Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages.

Malignant mesothelioma (MM) is a highly fatal tumor arising from inner body membranes, whose extensive growth is facilitated by its week immunogenicity and by its ability to blunt the immune response which should arise from the huge mass of leukocytes typically infiltrating this tumor. It has been reported that the inflammatory infiltrate found in MM tissues is characterized by a high prevalence of macrophages. Thus, in this work we evaluated the ability of human MM cells to modulate the inflammatory phenotype of human THP-1 monocytes and macrophages, a widely used in vitro model of monocyte/macrophage differentiation. Furthermore, we tested the hypothesis that the exposure to MM cells could alter the differentiation of THP-1 monocytes favoring the development of alternatively activated, tumor-supporting macrophages. Our data prove for the first time that MM cells can polarize monocytes towards an altered inflammatory phenotype and macrophages towards an immunosuppressive phenotype. Moreover, we demonstrate that monocytes cocultivated with MM cells 'keep a memory' of their encounter with the tumor which influences their differentiation to macrophages. On the whole, we provide evidence that MM cells exert distinct, cell-specific effects on monocytes and macrophages. The thorough characterization of such effects may be of a crucial importance for the rational design of new immunotherapeutic protocols.

Decrease of polyamine levels and enhancement of transglutaminase activity in selective reduction of B16-F10 melanoma cell proliferation induced by atrial natriuretic peptide.

The atrial natriuretic peptide (ANP) at physiological levels reduced the proliferation of highly metastatic murine (B16-F10) and human (SK-MEL 110) melanoma cell lines whereas rat aortic smooth muscle (RASM) cells were unaffected. In RASM cells, the levels of proliferation markers (putrescine, spermidine and spermine) increase after 24 h of epidermal growth factor (EGF) stimulation (RASM-EGF), but strongly decrease after 24 h of exposition to ANP. The B16-F10 cell line, which received no EGF stimulation, showed a similar decrease in polyamine content after ANP treatment. Furthermore, the enzymatic activity of a differentiation marker (transglutaminase) was increased for both RASM-EGF and B16-F10 cells after 24 h of treatment with 10(-10) mol/l ANP, concomitantly with the observed inhibition of polyamine biosynthesis and cell growth. Data obtained on B16-F10 cells treated with 8Br-GMPc or with an ANP analogue (cANF) support the involvement of the type C ANP receptor (NRP-C) in hormone effects. From the overall results, it appears that ANP may play a role in the inhibition of cellular growth under hyperproliferative conditions, as shown for RASM-EGF cells. The B16-F10 melanoma cell line showed similar results, but in the absence of mitogen stimulation. This observation suggests that the constitutive hyperproliferative state of tumor cells may be a sufficient condition to favor the ANP inhibitory effects on cell growth. This finding is particularly interesting in the light of a possible use of ANP as a potential selective antineoplastic agent.

Sphingosine 1-phosphate induces antimicrobial activity both in vitro and in vivo.

Sphingosine 1-phosphate (S1P), a polar sphingolipid metabolite, is involved in a wide spectrum of biological processes, including Ca(++) mobilization, cell growth, differentiation, motility, and cytoskeleton organization. Here, we show a novel role of S1P in the induction of antimicrobial activity in human macrophages that leads to the intracellular killing of nonpathogenic Mycobacterium smegmatis and pathogenic M. tuberculosis. Such activity is mediated by host phospholipase D, which favors the acidification of mycobacteria-containing phagosomes. Moreover, when it was intravenously injected in mycobacteria-infected mice, S1P reduced mycobacterial growth and pulmonary tissue damage. These results identify S1P as a novel regulator of the host antimicrobial effector pathways.