Suramin prevents binding of interleukin 2 to its cell surface receptor: a possible mechanism for immunosuppression.
Suramin, a polysulfonic naphthalene antihelminthic drug, inhibits proliferation of a variety of T-cell lines in vitro and induces immunosuppression in some human patients and thymic atrophy and splenic depletion in mice. Recent clinical trials indicate that suramin has activity against human tumors, indicating that it will be necessary to understand the mechanism by which suramin induces immunosuppression. The T-cell growth factor, interleukin 2 (IL2), is the major growth factor involved in regulating lymphoid differentiation and proliferation and thus regulates, to a major degree, the magnitude and duration of the immune response. We demonstrate herein that suramin induces a concentration-dependent decrease in binding of 125I-labeled IL2 to its receptor complex on human and murine T-lymphocytes. Binding of 125I-labeled IL2 to both Mr 75,000 and 55,000 IL2 binding molecules was inhibited by suramin. Similar concentrations of suramin were required to inhibit binding of 125I-labeled IL2, IL2-induced tyrosine phosphorylation, and IL2-induced proliferation, suggesting that these processes may be linked. With murine cells, suramin-induced growth inhibition could be overcome completely by increasing the concentration of IL2, suggesting that suramin inhibited growth by competing for the IL2 receptor. With human cells, growth inhibition by suramin could only be partially overcome by increasing the concentration of IL2, suggesting that an additional growth-inhibiting mechanism is present. The ability of suramin to prevent binding of IL2 to its receptor was used to confirm that prolonged interaction of IL2 with its receptor is required to induce cell proliferation. Since IL2 plays a role in lymphocyte proliferation and differentiation, the ability of suramin to inhibit binding of IL2 to its receptor may explain, in part, the in vivo immunosuppressive activities of suramin.
Mills
G B
GB
Oncology Research, Toronto General Hospital, Ontario, Canada.
Zhang
N
N
May
C
C
Hill
M
M
Chung
A
A
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation; D019000:Phosphotyrosine; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D013498:Suramin / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D019000:Phosphotyrosine; D014443:Tyrosine; D013498:Suramin