Activation of lymphokine genes in T cells: Role of cis-acting DNA elements that respond to T cell activation signals

Naoko Arai, Yoshiyuki Naito, Mitsuo Watanabe, Esteban S. Masuda, Yuko Yamaguchi-Iwai, Akio Tsuboi, Toshio Heike, Ikuo Matsuda, Kyoko Yokota, Naoko Koyano-Nakagawa, Hyun Jun Lee, Masaaki Muramatsu, Takashi Yokota, Ken Ichi Arai

Research output: Contribution to journalReview articlepeer-review

31 Scopus citations


Activation of T cells is iniated by the recognition of antigen on antigen presenting cells to exert the effector functions in immune and inflammatory responses. Two types of helper T cell (Th) clones (Th1 and Th2) are defined on the basis of different patterns of cytokine (lymphokine) secretion. They determine the outcome of an antigenic response toward humoral or cell-mediated immunity. Although lymphokine genes are coordinately regulated upon antigen stimulation, they are regulated by the mechanisms common to all as well as those which are unique to each gene. For most lymphokine genes, a combination of phorbol esters (phorbol 12-myristate 13 acetate, PMA) and calcium ionophores (A23187) is required for their maximal induction. Yet phorbol ester alone or calcium ionophore alone produce several lymphokines. The production of the granulocyte-macrophage colony stimulating factor (GM-CSF) is completely dependent on the two signals. We have previously found a cis-acting region spanning the GM-CSF promoter region (positions -95 to +27) that confers inducibility to reporter genes in transient transfection assays. Further analysis identified three elements required for efficient induction, referred to as GM2, GC-box and conserved lymphokine element (CLE0). GM2 defines a binding site for protein(s) whose binding is inducible by PMA. One protein, NF-GM2 is similar to the transcription factor NK-kB. GC-box is a binding site for constitutively bound proteins. CLE0 defines binding site for protein(s) whose optimum binding is stimulated by PMA and A23187. Viral rans-activators such as Tax (human T cell leukemia virus-1, HTLV-1) and E2 (bovine papilloma virus, BPV) proteins are other agents which activate lymphokine gene expression by bypassing T cell receptor (TCR) mediated signaling. The rans-activation domain of E2 and Tax is interchangeable although they have no obvious sequence homology between them. Teh viral trans-activators appear to target specific DNA binding protein such as NF-kB and Sp1 to cis-acting DNA site and promote lymphokine gene expression without TCR-mediated stimulation.

Original languageEnglish (US)
Pages (from-to)303-318
Number of pages16
JournalPharmacology and Therapeutics
Issue number3
StatePublished - 1992


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