CXCR3-binding chemokines in multiple myeloma
Introduction
Chemokines are small secretory proteins that are produced by leukocytes, epithelial, endothelial and stromal cells as they exert a chemotactic activity, mainly on leukocytes. They are grouped into two classes depending on the arrangement of the first two cysteines, namely separated by one amino acid (CXC chemokines) or adjacent (CC chemokines). Their biological effects are mediated by interaction with specific receptors (R), that are referred to as CXC-R and CC-R, respectively [1].
CXCR3 is expressed by activated T cells, i.e. IL-2-cultured T cells [2]. It is also expressed by tumor T cells of angioimmunoblastic, angiocentric, histiocyte-rich and unspecified T-cell lymphoma [3], and tumor B cells of chronic lymphocytic leukemia (CLL) and small cell lymphoma, but absent on normal B cells [4], [5]. It and its transcripts were not detected in monocytes, macrophages, granulocytes, and again normal B cells [4], [5]. It is specific for the CXC chemokines I-TAC (Interferon-inducible T-cell Alpha Chemoattractant)/CXCL11, Mig (Monocyte/macrophage-activating IFNγ-inducible protein)/CXCL9 and IP10 (IFNγ-inducible 10 kDa protein)/CXCL10 which are mainly produced by monocytes and macrophages [1], [2]. The CXCR3/CXC chemokine loop acts in inflammatory processes, mainly in delayed-type hypersensitivity responses, where the chemokines (the so called ‘homing chemokines’) mediate recruitment and homing of lymphocytes. The CXCR3/Mig loop may be important for the autocrine growth of CLL [5], and the CXCR3/chemokines loop facilitates progression and spreading of human melanoma and ovary carcinoma [6].
Here, we show that CXCR3 is expressed by plasma cells of multiple myeloma (MM), and activates cell functions (tyrosine-kinase phosphorylation, chemotaxis and matrix metalloproteinase [MMP] secretion) involved in the progression and spreading of disease.
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Patients and methods
The MM cell lines U266, DP-6, RPMI-8226 and K620 were obtained from the American Type Culture Collection (Rockville, MD, USA). Fresh bone marrow plasma cells were isolated from aspirates of 20 patients with newly diagnosed, staged II–III (Durie and Salmon) MM by Ficoll-Hypaque centrifugation and cell enrichment with CD38 immunoselection [7]. The study was approved by the local ethics committee and all patients gave their informed consent.
CXCR3 expression was determined in triplicate by
Results
Fig. 1 shows CXCR3 expression by the MM cell lines. Expression (M±1SD of three separate experiments) was found on 95%±4 U266 cells, 60% ±11 DP-6 cells, 82% ±5 RPMI-8226 cells and 15%±7 K620 cells. The expression was also studied on bone marrow plasma cells of 20 patients (Fig. 2): two patients (Pt3 and Pt11) (10%) expressed CXCR3 only marginally; 11 patients (55%) expressed CXCR3 in 20–50% plasma cells; seven patients (35%) expressed CXCR3 in more than 50% plasma cells. To sum up, 90% of
Discussion
Here we show that CXCR3 is expressed by several MM cell lines and fresh bone marrow plasma cells of newly-diagnosed MM. Similar results have been obtained with other MM cell lines by Moller et al. [11]. Expression has so far been described on activated T cells [2] but not normal peripheral B cells [4], [5], [12]. Like plasma cells, CXCR3 was also found on malignant B cells of CLL [4].
Its ligands I-TAC, Mig and IP10 induce chemotaxis of cells in the sites of chronic inflammation [13], and play
Acknowledgements
This study was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, and Ministry for Education, the Universities and Research (MIUR, Molecular Engineering—CO3 funds, and Interuniversity Funds for Basic Research [FIRB]), Rome, Italy.
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