Understanding the molecular mechanisms regulating the expression of interleukin 4 (IL-4) may shed light on the differentiation of lymphokine-producing phenotypes of CD4+ T cells. We have identified two DNA segments that are necessary for full phorbol 12-myristate 13-acetate (PMA)-induced activity of the IL-4 promoter region in the thymoma cell line EL4. Through deletion and mutation analyses, one of these segments (-57 through -47) was shown to be indispensable for promoter function. We designated this sequence consensus sequence 1 (CS1), as it shares homology with a sequence (ATTTTCCNNTG) that appears five times in the proximal 302-base-pair (bp) region 5' of the gene. We examined CS1 in further detail, as well as a second consensus sequence, CS2, located at nucleotides -75 through -65; both are within a minimal 83-bp construct that expresses full promoter activity. CS1- and CS2-spanning oligonucleotides bound apparently distinct PMA-inducible, sequence-specific factors in mobility-shift assays. Multimer constructs linking CS1- or CS2-spanning oligonucleotides to a heterologous promotor revealed that the CS1 construct had the greater enhancer activity in EL4 cells. Mutating the CS1 sequence within the context of the 302-bp promoter abolished all activity of the promoter, while mutating the CS2 sequence alone had little effect. Furthermore, a CS1 multimer could drive a heterologous promoter in an IL-4-producing [helper T-cell type 2 (TH2-type)] T-cell clone but not in a non-IL-4-producing (TH1-type) clone, suggesting a mechanism by which IL-4 production could be differentially regulated in TH subsets.

Animals↗

PubMed1992

The interleukin-4-related lymphokines and their binding to hematopoietin receptors.

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Animals↗

PubMed1992

CD8+ T cells can be primed in vitro to produce IL-4.

IL-4 production by T lymphocytes from naive mice in response to stimulation by plate-bound anti-CD3 is concentrated among CD4+ T cells. In vitro stimulation of lymph node T cells with anti-CD3 plus IL-2 and IL-4 strikingly increases the frequency of cells that produce IL-4 in response to subsequent stimulation with anti-CD3 plus IL-2. Separation of these primed cell populations into CD4+ and CD8+ T cell by cell sorting reveals that the frequency of IL-4-producing cells in both population is similar. Verification that CD8+ T cells produce IL-4 is provided by the capacity of anti-IL-4 mAb to inhibit the response of the indicator cell line to the growth factor produced by the primed cells and by detection of IL-4 by an IL-4-specific ELISA. The in vitro "priming" of CD8+ T cells to produce IL-4 is not dependent on the presence of CD4+ T cells because highly purified CD8+ T cells can be stimulated to develop into cells capable of producing IL-4 by culture with plate-bound anti-CD3 plus IL-2 and IL-4.

Animals↗

PubMed1992

The interleukin-4 family of lymphokines.

Evidence has accumulated indicating that four T-cell derived lymphokines, interleukin-4, interleukin-5, granulocyte-macrophage colony stimulating factor and interleukin-3, are closely related. The genes encoding these lymphokines are clustered within a region of 1000 kb, the proteins have a common secondary and spatial organization, and their corresponding receptors are all members of the haemopoietin family of receptors.

Amino Acid Sequence↗

PubMed1991

The snail gene required for mesoderm formation in Drosophila is expressed dynamically in derivatives of all three germ layers.

The zygotic effect gene snail (sna) encodes a zinc-finger protein required for mesoderm formation in Drosophila embryos. By in situ analysis, sna transcripts are first detected at syncytial blastoderm and persist until very late stages of embryogenesis. Expression of sna is transient and is observed in tissues derived from all three germ layers. Prior to germband elongation, sna RNA accumulation is consistent with its genetically determined role in mesoderm formation. Starting at germband elongation, a second phase of sna expression appears to be initiated, characterized by a highly dynamic accumulation of transcripts in the developing central and peripheral nervous systems. Translation of sna RNA is apparently delayed as the sna protein is not detected before the onset of gastrulation. Its regional distribution generally correlates with that of sna transcripts. The complex pattern of sna expression strongly suggests that the function of the gene is not restricted to mesoderm formation.

Animals↗

PubMedDate not supplied

The Drosophila developmental gene snail encodes a protein with nucleic acid binding fingers.

Pattern formation in the Drosophila embryo requires the concerted expression of maternal and zygotic genes. At least nineteen genes, twelve of which are maternally expressed, are involved in the establishment of dorsal-ventral polarity. Mutations in any one of these genes result in distinct alterations of cell fates and in the formation of an abnormal dorsal-ventral pattern. Mutants of the 'dorsal group', eleven of the maternal genes, have a common recessive phenotype similar to that described for dorsal, in that cells located at ventral and lateral positions assume dorsal fates and ventral structures fail to develop. Thus the dorsal group gene products may be involved in the establishment of a gradient of positional information along the dorsal-ventral axis. We have cloned snail (sna), a zygotic gene, whose expression is essential for the correct specification of dorsal-ventral pattern. In this report, we present evidence that the complementary DNA-deduced protein product of sna contains five copies of a nucleic acid-binding finger motif previously identified in two transcription factors, and in the protein product of several putative regulatory genes.

Amino Acid Sequence↗