Generation of a variant of human interleukin-4 by alternative splicing

Alms, William J.; Atamas, Sergei P.; Yurovsky, Vladimir V.; White, Barbara

doi:10.1016/0161-5890(95)00154-9

Cited by 58 publications

(32 citation statements)

References 42 publications

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“…A naturally occurring alternatively spliced variant of IL-4, termed IL-4d2 (IL-4d2), was identified in the 1990s, 13,14 and has subsequently been shown to occur naturally in humans, other primates, and various other species, including mice. [15][16][17] Interleukin-4d2 lacks the region encoded by the second exon for IL-4, and the corresponding part of the protein comprising 16 amino acids is absent.…”

Section: Discussionmentioning

confidence: 99%

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

et al. 2011

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Summary Interleukin‐4 (IL‐4) acts on cultured cells in a species‐specific fashion, although several reports have suggested that human (h) IL‐4 may be functionally active in rodents in vivo. The latter finding, if true, would not only offer possibilities for pre‐clinical testing of novel hIL‐4‐targeting therapies in animals, but also suggests new opportunities for mechanistic studies of IL‐4 and its receptors. Conventional IL‐4 is encoded by four exons, whereas its poorly studied alternatively spliced isoform is encoded by exons 1, 3 and 4 (IL‐4δ2). Replication‐deficient adenovirus‐mediated gene delivery of hIL‐4 isoforms (hIL‐4 or hIL‐4δ2) to mouse lungs caused similar pulmonary infiltration of T and B lymphocytes, but not eosinophils. There were significant differences in the changes of pulmonary cytokine milieu induced by hIL‐4 compared with hIL‐4δ2, with hIL‐4δ2 inducing higher levels of pro‐inflammatory (tumour necrosis factor‐α, IL‐1, and monocyte chemotactic protein‐1) and T helper type 1 (IL‐12 and interferon‐γ) cytokines. There was no elevation in endogenous mouse (m) IL‐4 or mIL‐4δ2 mRNAs, and germ‐line deficiency of mIL‐4 did not affect the degree of pulmonary infiltration. When combined with an ovalbumin model of asthma, hIL‐4δ2 stimulated a greater accumulation of lymphocytes than did hIL‐4. Pulmonary infiltration of lymphocytes induced by expression of hIL‐4 or hIL‐4δ2 was attenuated, but not completely abrogated, by germ‐line deficiency of mIL‐4Rα or murine signal transducer and activator of transcription 6, suggesting that these signalling molecules mediate the in vivo effects of hIL‐4 isoforms in mice. These findings suggest that splice isoforms of human IL‐4 are functionally active in vivo in mice, and partially share the effects of the corresponding species‐specific isoforms.

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Section: Discussionmentioning

confidence: 99%

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

et al. 2011

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“…Alms et al [24] described a new mechanism for the regulation of IL-4 activity, in which a second mRNA is alternatively spliced from the nuclear IL-4 RNA, deleting intron 2. The spliced mRNA is translated to IL-4 delta 2 cytokine.…”

Section: Alternative Splicing Of the Il-4 Gene Generates Il-4 Delta 2mentioning

confidence: 99%

“…Figure 1 details the molecular events and the effects of HIV-1 infection of the Thl and Th2 cytokines in an infected person that produces more IL-4 than IL-4 delta 2 cytokines (e.g. ratio of 16:1, [24]). Figure 2 presents the molecular events during HIV-1 infection in a person that produces more IL-4 delta 2 than IL-4 cytokines (e.g.…”

Section: Alternative Splicing Of the Il-4 Gene Generates Il-4 Delta 2mentioning

confidence: 99%

“…Figure 2 presents the molecular events during HIV-1 infection in a person that produces more IL-4 delta 2 than IL-4 cytokines (e.g. ratio 2:1 [24]) . Avensa et al [25] reported that an engineered mutation that changed Tyr (124) to Asp is a synthetic IL-4 antagonist since the mutation is at the base of helix D, which forms part of the second receptor binding site for IL-4. This IL-4 mutant protein inhibited in human B cells the IL-4 induced IgG4 and IgE synthesis.…”

Section: Alternative Splicing Of the Il-4 Gene Generates Il-4 Delta 2mentioning

confidence: 99%

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The Molecular Mechanism of Human Resistance to HIV-1 Infectionin Persistently Infected Individuals—A Review, Hypothesis and Implications

Becker

2005

Virus Genes

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Resistance to HIV-1 infection in Europeans is associated with a mutation in the gene that codes for the CCR5 protein that is present in Th2 cells and serves as a coreceptor for HIV-1 R5 strain. A deletion of 32 amino acids from the cytokine receptor prevents infection. This mutation prevails in Europeans and is absent in Africans. However, duplication of a gene that codes for a chemokine that binds to the CCR5 was discovered in Africans (mean gene copy 6 while in non-Africans the mean gene copy is 3). Higher expression of these genes protects T cells against HIV-1 infection in vitro. It should be noted that resistance to HIV-1 R5 variant does not protect against HIV-1 R4 variant. It was reported that a minority of highly HIV-1 exposed African professional sex workers (APSW) were resistant to the virus infection during a 10 years period. Recently, the analysis of the cytokines in the serum of the persistently infected seronegative women revealed that the latter hypo-expresses the cytokine IL-4. Since the molecular events during HIV-1 infection are associated with a marked increase in the levels of IL-4 and IgE in the sera of the infected individuals, it suggests that AIDS is an allergy. Thus, a very low level of IL-4 production may abrogate the virus infection. Studies on the human IL-4 gene revealed that together with the IL-4 mRNA a spliced variant with a deletion of exon 2 is synthesized. The latter is a natural antagonist of IL-4 and when expressed in an individual at a level higher than IL-4, the person will resist a microbial infection (e.g. Mycobacterium tuberculosis) or asthma. The present hypothesis suggests that the HIV-1 resistant APSWs produce more IL-4 delta 2 molecules than IL-4 molecules. The binding of IL-4 delta 2 to IL-4 receptors on T and B cells prevents their functions and the infection by HIV-1. The implications of these studies are that treatment of HIV-1 infected people with drugs that will block the IL-4 receptors will stop HIV-1 infections and the determination of the levels of IL-4 and IL-4 delta 2 in the sera of HIV-1+ patients will enable to identify the individuals that have a natural resistance to HIV-l/AIDS and those who need treatments.

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“…Alternative splicing of IL-4 mRNA yields a splice variant with deletion of exon 2: IL-4δ2 [1,10]. The expression of IL-4δ2 mRNA is tissue-specific and was detected in human peripheral blood mononuclear cells (MNC), amygdala, bronchoalveolar lavage fluid, lungs, intestine, and thymus.…”

mentioning

confidence: 98%