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Specific Inhibition of Interleukin 1ß Gene Expression by an Antisense Oligonucleotide: Obligatory Role of Interleukin 1 in the Generation of Lymphokine-activated Killer Cells¹

Departments of Tumor Biology [T. F., E. A. G.] and General Surgery [E. A. G.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The purpose of the studies reported here is to determine whether interleukin 1 (IL-1) plays an important role in the regulation of lymphokine-activated killer (LAK) cell induction. The addition of exogenous IL-1 to peripheral blood lymphocyte cultures containing suboptimal concentrations of interleukin 2 (IL-2) resulted in induction of cytoplasmic pore-forming protein expression. Polymerase chain reaction results revealed that the mRNAs of both IL-1 and IL-1ß were induced within 6 h when cultured in IL-2 alone or in a combination of IL-2 and IL-1; however, tumor necrosis factor and ß mRNAs were expressed earlier in peripheral blood lymphocytes stimulated with the combination of IL-1 and IL-2. Furthermore, we have examined the functional role of endogenous IL-1 in LAK activity. The lytic potential was significantly inhibited by an IL-1 receptor antagonist, which could block IL-1-mediated effects, or by specific neutralizing antibodies for IL-1, suggesting that the extracellular autocrine/paracrine pathway of IL-1 is involved in LAK activation. However, a synthetic IL-1ß antisense oligonucleotide, which could specifically inhibit intracellular IL-1ß protein expression as detected by Western blot, was more effective in reducing LAK killing, but it could not suppress the cytotoxicity generated by exogenous IL-1 plus IL-2. These findings clearly indicate the existence of an intracellular IL-1 autocrine circuit. Taken together, our results strongly indicate that IL-1 should be considered an obligatory factor in the regulation of IL-2-mediated lymphocyte functions.

¹ This work was supported by NIH Grant CA45225 to E. A. G.

² To whom requests for reprints should be addressed, at Department of Tumor Biology, Box 79, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 2/ 7/92. Accepted 7/ 9/92.

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