Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Carpintero, Rakel; Brandt, Karim J.; Gruaz, Lyssia; Molnarfi, Nicolas; Lalive, Patrice H.; Burger, Danielle

doi:10.1073/pnas.1009443107

Cited by 29 publications

(26 citation statements)

References 55 publications

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“…An earlier study showed the ability of GA to induce sIL-1Ra expression via the activation of PI3K, AKt, MEK1/2, and ERK1/2 [55]. However, PD-98059 (10 mM) was not found to Cellular Physiology and Biochemistry…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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Background/Aims: Immunological mechanisms can be triggered as a response to central nervous system insults and can lead to seizures. In this study an investigation was made to determine if glatiramer acetate (GA), an immunomodulator currently used in the treatment of multiple sclerosis, could protect rats from pilocarpine-induced seizures and chronic epilepsy. Methods: Two groups of adult male Sprague-Dawley rats, experimental (GA) and control, were used in the study. The systemic IL-1α and IL-1β levels at baseline were checked as well as status epilepticus (SE), and the spontaneous recurrent seizure (SRS) stage by enzyme-linked immunosorbent assay. The GA group was given GA (150 μg/kg, ip) and the control group was given a saline injection prior to pilocarpine-induced seizures. Seizure susceptibility, severity and mortality were evaluated, using Racine seizure classification and hippocampal damage was evaluated by Nissl staining. The GA group received GA (150 μg/kg/day, ip) daily after SE, and the chronic spontaneous seizures were evaluated by long-term video recording, and mossy fiber sprouting was evaluated by Timm staining. The IL-1α and IL-1β levels were correlated with seizure activities. The TNF-α level in the hippocampus was determined at the SRS stage by immunohistochemistry. The effect of GA on ionic currents and action potentials (APs) in NG108-15 differentiated neurons was investigated using patch-clamp technology. Results: It was found that latency to severe seizures was significantly longer in the GA (p < 0.01) group, which also had SE of shorter duration and less frequent SRS (p < 0.01). GA attenuated acute hippocampal neuron loss and chronic mossy fiber sprouting in the CA3 and the SRS-reduction correlated with the reduction of IL-1α, but not with IL-1β or TNF-α levels. Mechanistically, GA reduced the peak amplitude of voltage-gated Na⁺ current (I_Na), with a negative shift in the inactivation curve of I_Na and reduced the amplitude of APs along with decreased firing of APs. Conclusion: GA might serve as a neuroexcitability modulator which attenuates pilocarpine-induced acute and chronic excitotoxicity. Sodium channel attenuation was partially independent of the immunomodulatory effect.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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“…There is also evidence to suggest that GA, in addition to its action on the adaptive immune system, acts on the innate immune system by directly modulating the activity of myeloid cells, in particular monocytes and dendritic cells [39][40][41][42]. The properties of monocytes of RRMS patients undergoing treatment with GA have been compared with those of untreated patients and of healthy controls, showing that monocyte reactivity was inhibited in the treated patients.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

The heritage of glatiramer acetate and its use in multiple sclerosis

Comı

Amato

Bertolotto

et al. 2016

Mult Scler Demyelinating Disord

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Multiple sclerosis (MS) is a chronic and progressively debilitating disease of the central nervous system. Treatment of MS involves disease-modifying therapies (DMTs) to reduce the incidence of relapses and prevent disease progression. Glatiramer acetate (Copaxone®) was the first of the currently approved DMTs to be tested in human subjects, and it is still considered a standard choice for first-line treatment. The mechanism of action of glatiramer acetate appears to be relatively complex and has not been completely elucidated, but it is likely that it involves both immunomodulating and neuroprotective properties. The efficacy of glatiramer acetate 20 mg/mL once daily as first-line treatment in relapsingremitting MS is well established, with ample evidence of efficacy from both placebo-controlled and active-comparator controlled clinical trials as well as real-world studies. There is also a considerable body of evidence indicating that the efficacy of glatiramer acetate is maintained in the long term. Clinical trial and real-world data have also consistently shown glatiramer acetate to be safe and well tolerated. Notably, glatiramer acetate has a good safety profile in women planning a pregnancy, and is not associated with foetal toxicity. Until recently, glatiramer acetate was only approved as 20 mg/mL once daily, but a new formulation with less frequent administration, 40 mg/mL three times weekly, has been developed and is now approved in many countries, including Italy. This review examines the mechanism of action, clinical efficacy, safety and tolerability of glatiramer acetate to provide suggestions for optimizing the use of this drug in the current MS therapeutic scenario.

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“…43 IL-1b, in turn, induces specifically the expressions of IL-1b and sIL-1Ra, as shown in cultured human endometrial stromal cells. 44 In diabetic tissues, such as the cornea, impairment of PI3K and ATK signaling, because of impaired epidermal growth factor receptor signaling, 25 may differentially affect sIL-1Ra production, as shown in human monocytes, 45 resulting in an imbalance of IL-1b and sIL-1Ra, leading to delayed epithelial wound healing (Figure 9).…”

Section: Il-1ra and Diabetic Cornea Wound Healingmentioning

confidence: 99%

Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

Yan

Gao

Sun

et al. 2016

The American Journal of Pathology

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fanxq@sh163. net.Patients with diabetes mellitus often develop corneal complications and delayed wound healing. How diabetes might alter acute inflammatory responses to tissue injury, leading to delayed wound healing, remains mostly elusive. Using a streptozotocin-induced type I diabetes mellitus mice and corneal epithelium-debridement wound model, we discovered that although wounding induced marked expression of IL-1b and the secreted form of IL-1 receptor antagonist (sIL-1Ra), diabetes suppressed the expressions of sIL-1Ra but not IL-1b in healing epithelia and both in whole cornea. In normoglycemic mice, IL-1b or sIL-1Ra blockade delayed wound healing and influenced each other's expression. In diabetic mice, in addition to delayed reepithelization, diabetes weakened phosphatidylinositol 3-kinaseeAkt signaling, caused cell apoptosis, diminished cell proliferation, suppressed neutrophil and natural killer cell infiltrations, and impaired sensory nerve reinnervation in healing mouse corneas. Local administration of recombinant IL-1Ra partially, but significantly, reversed these pathological changes in the diabetic corneas. CXCL10 was a downstream chemokine of IL-1beIL-1Ra, and exogenous CXCL10 alleviated delayed wound healing in the diabetic, but attenuated it in the normal corneas. In conclusion, the suppressed early innate/inflammatory responses instigated by the imbalance between IL-1b and IL-1Ra is an underlying cause for delayed wound healing in the diabetic corneas. Local application of IL-1Ra accelerates reepithelialization and may be used to treat chronic corneal and potential skin wounds of diabetic patients. (Am J Pathol 2016 http://dx

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Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Cited by 29 publications

References 55 publications

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

The heritage of glatiramer acetate and its use in multiple sclerosis

Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

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