Interleukin 13 Is Secreted by and Stimulates the Growth of Hodgkin and Reed-Sternberg Cells

Abstract

Gene expression patterns can provide vital clues to the pathogenesis of neoplastic diseases. We investigated the expression of 950 genes in Hodgkin's disease (HD) by analyzing differential mRNA expression using microarrays. In two independent microarray experiments, the HD-derived cell lines L428 and KMH2 were compared with an Epstein-Barr virus (EBV)-immortalized lymphoblastoid B cell line, LCL-GK. Interleukin (IL)-13 and IL-5 were found to be highly expressed in the HD-derived cell lines. Examination of IL-13 and IL-5 expression by Northern blot analysis and enzyme-linked immunosorbent assay confirmed these results and revealed the expression of IL-13 in a third HD-derived cell line, HDLM2. Control LCL and EBV-negative non-Hodgkin lymphoma–derived cell lines did not express IL-13. In situ hybridization of lymph node tissue from HD patients showed that elevated levels of IL-13 were specifically expressed by Hodgkin/Reed-Sternberg (H/RS) tumor cells. Treatment of a HD-derived cell line with a neutralizing antibody to IL-13 resulted in a dose-dependent inhibition of H/RS cell proliferation. These data suggest that H/RS cells produce IL-13 and that IL-13 plays an important role in the stimulation of H/RS cell growth, possibly by an autocrine mechanism. Modulation of the IL-13 signaling pathway may be a logical objective for future therapeutic strategies.

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

“…25 Furthermore, interleukin 13 (IL-13) and its receptor have been shown to be frequently expressed in cultured and primary HRS cells. 27 Treatment of cultured HRS cells with IL-13-neutralizing antibodies resulted in a dosedependent proliferation arrest, indicating IL-13 involvement in HRS cell growth. 27 Similarly, IL-3 and IL-9 are functionally expressed in HRS cells and promote their proliferation.…”

“…27 Treatment of cultured HRS cells with IL-13-neutralizing antibodies resulted in a dosedependent proliferation arrest, indicating IL-13 involvement in HRS cell growth. 27 Similarly, IL-3 and IL-9 are functionally expressed in HRS cells and promote their proliferation. 26 Whether one of these secreted factors mediates its effects through activation of alternative NF-kB signaling in HRS cells, and whether aberrant Notch signaling might even control its expression requires further investigations.…”

“…It is known that HRS cells abundantly secrete soluble factors, such as cytokines and chemokines, and that they are involved in forming the particular microenvironment in cHL, and trigger HRS cell proliferation and survival. 14,[25][26][27] We incubated HRS cells with fresh or conditioned medium of untreated L540cy, L1236, KM-H2 and L428 cells, and simultaneously added GSI XII for 24 h. NF-kB p52 levels, which are indicative for alternative NF-kB signaling, remained stable in L540cy cells upon stimulation of cells with conditioned medium (Figure 5a, upper panel). Accordingly, conditioned medium efficiently reversed the loss of cell viability of GSI-treated HRS cells (Figure 5a, lower panel and Supplementary Figures S2A and B).…”

Stimulation of interleukin-13 expression by human T-cell leukemia virus type 1 oncoprotein Tax via a dually active promoter element responsive to NF-κB and NFAT

“…For instance, IL-13 overexpression in the malignant Reed-Sternberg (RS) cells of Hodgkin's lymphoma (HL) (Kapp et al, 1999;Skinnider et al, 2001Skinnider et al, , 2002, which causes the growth-promoting autostimulation, may be triggered by NF-kB via IL13TaxRE. This notion is supported by the strong constitutive activation of NF-kB in HL cell lines (Bargou et al, 1996) and in primary HL/RS cells (Bargou et al, 1997;Jost & Ruland, 2007), as well as by the identification of IL-13 as an NF-kB target in HL cells (Hinz et al, 2002;Jost & Ruland, 2007;Mathas et al, 2003).…”

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

“…24,25 It is critical for tumor immunosurveillance 26,27 and modulates apoptosis or tumor cell growth. 28,29 Two different components of the IL-13 receptor have been identified, which are known as IL-13R 1 chain [30][31][32] and IL-13R 2 chain. 33,34 IL-13R 1 chain alone binds IL-13 with low affinity.…”