Preclinical evaluation of recombinant human interleukin-4

Cornacoff, Joel B.; Gossett, Kent A.; Barbolt, Thomas A.; Dean, Jack H.

doi:10.1016/0378-4274(92)90202-u

Cited by 10 publications

(4 citation statements)

References 21 publications

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“…Significantly, we identified an increased intragraft expression of IL-4 and showed that neutralizing IL-4 in addition to anti-CD154 and anti-CD8 antibody treatment virtually abrogated intimal proliferation, underlining the proarterioslcerotic effect of IL-4 in this aortic transplant model. The data presented here are consistent with the hypothesis that IL-4 may directly induce vasculopathy (23). The biological activity of IL-4 is mediated through the heterodimeric IL-4 receptor, with IL-4 binding with high affinity to the IL-4 receptor ␣ chain (IL-4R␣).…”

Section: Discussionsupporting

confidence: 90%

Neutralizing Interleukin-4 Prevents Transplant Arteriosclerosis Mediated by Indirect Pathway T Cells Under CD40-CD154 Costimulation Blockade

et al. 2008

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Prolonged treatment with anti-CD154 was not able to prevent the development of transplant arteriosclerosis in MHC class I-mismatched aortic allografts, in the presence or absence of CD8+ T cells. This CD40-CD154 pathway resistant transplant arteriosclerosis was mediated by IL-4, because neutralizing IL-4 in addition to CD40-CD154 costimulation blockade and CD8+ T-cell depletion prevented its development.

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Section: Discussionsupporting

confidence: 90%

Neutralizing Interleukin-4 Prevents Transplant Arteriosclerosis Mediated by Indirect Pathway T Cells Under CD40-CD154 Costimulation Blockade

et al. 2008

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“…A direct effect of IL-4 on the vasculature has also been demonstrated in a preclinical evaluation of recombinant human IL-4. The administration of recombinant human IL-4 to cynomolgus monkeys resulted in dose-depending toxic effects and the varying occurrence of chronic arteritis, which was frequently associated with medial smooth muscle cell proliferation and an infiltration of eosinophils (43).…”

Section: Discussionmentioning

confidence: 99%

Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation

Ensminger

Spriewald

Sorensen

et al. 2001

The Journal of Immunology

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Blockade of the CD40-CD154 pathway can inhibit CD4+ T cell activation but is unable to prevent immune responses mediated by CD8+ T cells. However, even in the absence of CD8+ T cells, inhibition of the CD40-CD154 pathway is insufficient to prevent the development of transplant arteriosclerosis. This study investigated the mechanisms of transplant arteriosclerosis in the absence of the CD40 pathway. C57BL/6 CD40−/− (H2b) recipients were transplanted with MHC-mismatched BALB/c (H2d) aortas. Transplant arteriosclerosis was evident in both CD40−/− and CD40+/− mice (intimal proliferation was 59 ± 5% for CD40−/− mice vs 58 ± 4% for CD40+/− mice) in the presence or absence of CD8+ T cells (intimal proliferation was 46 ± 7% for CD40−/− anti-CD8-treated mice vs 50 ± 10% for CD40+/− anti-CD8-treated mice), confirming that CD8+ T cells are not essential effector cells for the development of this disease. In CD40−/− recipients depleted of CD8+ T cells, the number of eosinophils infiltrating the graft was markedly increased (109 ± 24 eosinophils/grid for CD40−/− anti-CD8-treated mice vs 28 ± 7 for CD40+/− anti-CD8-treated mice). The increased presence of eosinophils correlated with augmented intragraft production of IL-4. To test the hypothesis that IL-4 was responsible for the intimal proliferation, CD8 T cell-depleted CD40−/− recipients were treated with anti-IL-4 mAb. This resulted in significantly reduced eosinophil infiltration into the graft (12 ± 5 eosinophils/grid for CD40−/− anti-CD8+, anti-IL-4-treated mice vs 109 ± 24 for CD40−/− anti-CD8-treated mice), intragraft eotaxin, CCR3 mRNA production, and the level of intimal proliferation (18 ± 5% for CD40−/− anti-CD8+-, anti-IL-4-treated mice vs 46 ± 7% for CD40−/− anti-CD8-treated mice). In conclusion, elevated intragraft IL-4 production results in an eosinophil infiltrate and is an important mechanism for CD8+ T cell-independent transplant arteriosclerosis in the absence of CD40-CD154 costimulation.

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“…Clinical investigations of this cytokine are in progress. [6,10] The toxic side effects of IL-4 have to be further investigated. We investigated its cell growth suppression and the receptor mechanism in primary isolated and immortalized (tumor-derived) cell culture models.…”

Section: Introductionmentioning

confidence: 99%

Mono- Or Dual-Phosphorylation of Akt Kinase Is Regulated by Distinct Receptors That Involve the Common Insulin Receptor Substrate

Schnyder

Lahm

Pittet

et al. 2002

Journal of Receptors and Signal Transduction

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We have previously shown that the interleukin (IL)-4 signal transduction involves the Insulin Receptor Substrate (IRS) in human colorectal carcinoma cells LS513. In the present study it was tested whether IL-4 counters Insulin-like Growth Factor (IGF)-1 through competition at the IRS signal transduction pathway and, thus, induces a molecular "insulin resistance" or whether IL-4 invokes an alternative signal transduction. The activated receptors of IL-4 and IGF-I both docked to IRS-1 and IRS-2 and invoked IRS complex formation with phosphatidylinositol (PI) 3-kinase, as assessed by immunoprecipitation and detection of the precipitated compounds by immunoblot analysis. Both, IL-4 and IGF-1, signaling pathways induced phosphorylation of Akt kinase in a PI 3-kinase-dependent manner, as assessed by addition of the PI 3-kinase inhibitor Ly294002. Interleukin-4 stimulation induced mono-phosphorylation at serine residue S473 of Akt kinase but failed to activate the kinase. Insulin-like growth factor-1 stimulation invoked dual-phosphorylation at S473 and T308 of Akt kinase and subsequent activation of the kinase. When LS513 cells were treated with IL-4 to induce mono-phosphorylation of Akt, dual- phosphorylation and activation of Akt kinase in response to IGF-1 were still intact. Interleukin-4 yet reduced cell growth by at least 50% both, in the absence and presence of growth factor IGF-1. In the LS513 cells, IL-4 stimulated phosphorylation of Jak2, an adapter molecule at the IL-4 receptor, and phosphorylation of transcription factor Stat6 both, in the absence and presence of IGF-1. We found a similar IL-4 signal transduction and growth suppression in multiple human cell cultures, including primary cells. Our findings indicate that the molecular mechanism underlying growth suppression by IL-4 may depend on gene-expression but not on "insulin/growth factor resistance" at IRS.

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Preclinical evaluation of recombinant human interleukin-4

Cited by 10 publications

References 21 publications

Neutralizing Interleukin-4 Prevents Transplant Arteriosclerosis Mediated by Indirect Pathway T Cells Under CD40-CD154 Costimulation Blockade

Neutralizing Interleukin-4 Prevents Transplant Arteriosclerosis Mediated by Indirect Pathway T Cells Under CD40-CD154 Costimulation Blockade

Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation

Mono- Or Dual-Phosphorylation of Akt Kinase Is Regulated by Distinct Receptors That Involve the Common Insulin Receptor Substrate

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