IN RESPONSE:
Dr. Kubonishi and colleagues describe high serum levels of interleukin-6 in two patients with aggressive Ki-1 lymphoma. They further demonstrate that expression of interleukin-6 RNA and protein is absent in cell lines derived from these two patients, whereas expression of RNA for the interleukin-6 receptor is present. In addition, interleukin-6 could stimulate proliferation of the patients' lymphoma cells in vitro, suggesting a paracrine growth mechanism.
These results are of interest. We have shown that high serum interleukin-6 levels are present and that they correlate with poor prognosis in both Hodgkin and non-Hodgkin lymphoma [1-3]. Indeed, in diffuse large-cell lymphoma, interleukin-6 seems to be the most significant independent prognostic variable selected by multivariate analysis for prediction of both complete remission and failure-free survival [3]. Whether an autocrine or a paracrine mechanism is most significant is unclear, but both may be operative. For instance, Voorzanger and associates [4] used immunohistochemical methods to show that 89% of the non-Hodgkin lymphoma tumor samples that they studied were positive for interleukin-6 expression in both tumor cells and macrophages. Yee and coworkers [5] have shown interleukin-6 production and the use of interleukin-6 in an autocrine fashion for growth in two lymphoma cell lines. Taken together, these data suggest 1) an autocrine and paracrine role for endogenous interleukin-6 in lymphoma and 2) that the contribution of these alternative mechanisms to tumor proliferation may vary from patient to patient and between lymphoma subtypes. Future investigations should aim to identify the prognostic value of interleukin-6 in other lymphoproliferative disorders, to determine whether serum interleukin-6 levels can predict early relapse, and to develop interleukin-6 antagonists for the treatment of these lymphomas.
1. Seymour JF, Talpaz M, Hagemeister FB, Cabanillas F, Kurzrock R. Clinical correlates of elevated serum levels of interleukin-6 in patients with untreated Hodgkin's disease. Am J Med. 1997; 102:21-8.
2. Seymour JF, Talpaz M, Cabanillas F, Wetzler M, Kurzrock R. Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. J Clin Oncol. 1995; 13:575-82.
3. Preti HA, Cabanillas F, Talpaz M, Tucker SL, Seymour JF, Kurzrock R. Prognostic value of serum interleukin-6 in diffuse large-cell lymphoma. Ann Intern Med. 1997; 127:186-94.
4. Voorzanger N, Touitou R, Garcia E, Delecluse HJ, Rousset F, Joab I, et al. Interleukin (IL)-10 and IL-6 are produced in vivo by non-Hodgkin's lymphoma cells and act as cooperative growth factors. Cancer Res. 1996; 56:5499-505.
5. Yee C, Biondl A, Wang XH, Iscove NN, de Sousa J, Aarden LA, et al. A possible autocrine role for interleukin-6 in two lymphoma cell lines. Blood. 1989; 74:798-804.
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