Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia

The release of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and nitric oxide by microglia has been implicated in neurotoxicity in chronic neurodegenerative diseases such as Alzheimer's disease. As all-trans-retinoic acid (RA) has been reported to exert anti-inflammatory actions in various cell types, we have examined its effects on the expression of TNF-alpha and inducible nitric oxide synthase (iNOS) in microglia activated by beta-amyloid peptide (Abeta) and lipopolysaccharide (LPS). Exposure of primary cultures of rat microglial cells to Abeta or LPS stimulated the mRNA expression level of TNF-alpha (6-116-fold) and iNOS (8-500-fold) significantly. RA acted in a dose-dependent manner (0.1-10 microM) by attenuating both TNF-alpha (29-97%) and iNOS (61-96%) mRNA expression in microglia exposed to Abeta or LPS. RA-induced inhibition of TNF-alpha and iNOS mRNA expression in activated microglia was accompanied by the concomitant reduction in release of iNOS and TNF-alpha proteins as revealed by nitrite assay and ELISA, respectively. The anti-inflammatory effects of RA were correlated with the enhanced expression of retinoic acid receptor-beta, and transforming growth factor-beta1 as well as the inhibition of NF-kappaB translocation. These results suggest that RA may inhibit the neurotoxic effect of activated microglia by suppressing the production of inflammatory cytokines and cytotoxic molecules.     

HIV-1-infected and/or immune activated macrophages regulate astrocyte SDF-1 production through IL-1beta

Stromal cell-derived factor 1 alpha (SDF-1alpha) and its receptor CXCR4 play important roles in the pathogenesis of human immunodeficiency virus type one (HIV-1)-associated dementia (HAD) by serving as a HIV-1 co-receptor and affecting cell migration, virus-mediated neurotoxicity, and neurodegeneration. However, the underlying mechanisms regulating SDF-1 production during disease are not completely understood. In this report we investigated the role of HIV-1 infected and immune competent macrophage, the principal target cell and mediator of neuronal injury and death in HAD, in regulating SDF-1 production by astrocytes. Our data demonstrated that astrocytes are the primary cell type expressing SDF-1 in the brain. Immune-activated or HIV-1-infected human monocyte-derived-macrophage (MDM) conditioned media (MCM) induced a substantial increase in SDF-1 production by human astrocytes. This SDF-1 production was directly dependent on MDM IL-1beta following both viral and immune activation. The MCM-induced production of SDF-1 was prevented by IL-1beta receptor antagonist (IL-1Ra) and IL-1beta siRNA treatment of human MDM. These laboratory observations were confirmed in severe combined immunodeficient (SCID) mice with HIV-1 encephalitis (HIVE). In these HIVE mice, reactive astrocytes showed a significant increase in SDF-1 expression, as observed by immunocytochemical staining. Similarly, SDF-1 mRNA levels were increased in the encephalitic region as measured by real time RT-PCR, and correlated with IL-1beta mRNA expression. These observations provide direct evidence that IL-1beta, produced from HIV-1-infected and/or immune competent macrophage, induces production of SDF-1 by astrocytes, and as such contribute to ongoing SDF-1 mediated CNS regulation during HAD.     

Effects of IL-1beta, IL-6 or LIF on rat sensory neurons co-cultured with fibroblast-like cells.

Inflammation may affect the local presence of sensory nerve fibers in situ and inflammatory mediators influence sensory neurons in vitro. In the present study we have investigated effects of the cytokines interleukin-1beta (IL-1beta, interleukin-6 (IL-6), and leukemia inhibitory factor (LIF) on survival of and neurite growth from neonatal rat sensory neurons co-cultured with fibroblast-like cells prepared from neonatal rat skin (sFLCs) or perichondrium (pFLCs). The results showed that both FLC types expressed receptors for all three cytokines. Five ng/ml of either cytokine, but not lower or higher concentrations, supported survival of DRG neurons co-cultured with sFLCs. Neuronal survival was also enhanced by addition of the soluble IL-6 receptor (rsIL-6R) with or without IL-6. In co-cultures with pFLCs neuronal survival was promoted by IL-6, increasing with cytokine concentration. Addition of rsIL-6R without IL-6 did also stimulate neuronal survival. The growth of neurites from DRG neurons co-cultured with sFLCs was stimulated by 0.5 ng/ml LIF, unaffected by 5 ng/ml LIF and inhibited by 50 ng/ml LIF. Considering DRG neurons co-cultured with pFLCs, 50 ng/ml of either of the three cytokines, as well as rsIL-6R conditioned medium, stimulated neurite outgrowth. Some of the cytokine effects observed were reduced by application of antibodies against nerve growth factor (NGF). We conclude that that the cytokines examined affect DRG neurons in terms of survival or neuritogenesis, that the effects are influenced by cytokine concentration and the origin of the FLCs and that some of the effects are indirect, probably being mediated by factors released from FLCs.     

Contribution of the interleukin-1beta gene polymorphism in multiple system atrophy.

We studied genetic polymorphisms in the promoter region at position -511 of the interleukin (IL) -1beta gene (IL-1B-511) and at position -889 of the IL-1alpha gene (IL-1A-889), in 111 Japanese patients with multiple system atrophy (MSA) and 160 controls. The distribution of IL-1B-511 was significantly different between MSA patients and controls, because of the under-representation of patients with homozygotes for allele 2 (IL-1B-511*2), a high producer of IL-1beta. The frequency of IL-1A-889*2, a high secretor of IL-1alpha, was also decreased in MSA patients. Our findings suggest that abnormal cytokine expression may be implicated in the pathogenesis of MSA.     

Japanese Encephalitis Virus infection induces IL-18 and IL-1beta in microglia and astrocytes: correlation with in vitro cytokine responsiveness of glial cells and subsequent neuronal death

IL-1β and IL-18 are members of the IL-1 family of ligands, and their receptors are members of the IL-1 receptor family. Although several biological properties overlap for these cytokines, differences exist. In order to assess functional importance of these two cytokines in viral encephalitis, we have exploited an experimental model of Japanese Encephalitis (JE) and subsequent in vitro cell culture system. We report for the first time that in Japanese Encephalitis, microglia and astrocytes both produce IL-18 and IL-1β. In vitro, these two cytokines differentially activate microglia and astrocyte, and also alter the by stander neuronal survival following treatment with these two cytokines.     

Transforming growth factor beta1 prevents IL-1beta-induced microglial activation,whereas TNFalpha- and IL-6-stimulated activation are not antagonized

Microglia rapidly respond to CNS injury, yet the mechanisms leading to their activation and inactivation remain poorly defined. In particular, few studies have established how interactions between inflammatory mediators affect the innate immune response of microglia. To begin to establish how microglia integrate signals from multiple inflammatory mediators, we examined the effects of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), interferon gamma (IFN-gamma), and transforming growth factor beta1 (TGFbeta1) on both newborn and bulk-isolated adult microglia. To assess the functional state of the cells, we assayed the expression of cyclooxygenase 2 (Cox-2), interleukin 6, and tumor necrosis factor alpha, and two protein tyrosine kinases that have been implicated in microglial responses to activational stimuli, HCK and FAK. These studies demonstrated that IL-1beta, TNFalpha, IL-6, but not IFN-gamma increase the expression of Cox-2, whereas they all increase the expression of HCK and FAK. In these studies, TGFbeta1 either had no effect, or it decreased basal levels of these proteins. TGFbeta1 blocked activation by IL-1beta when given prior to, or simultaneously with, IL-1beta. TGFbeta1 blocked the induction of the tyrosine kinases, Cox-2, and the induction of IL-6 and TNFalpha mRNAs. However, TGFbeta1 was ineffective in antagonizing the induction of Cox-2 by either IL-6 or TNFalpha. We conclude that the TGFbeta receptor signaling cascades intersect with IL-1, but they may not interact with IL-6 or TNFalpha signaling pathways that lead to activation.     

IL‐12 p40 homodimer,the so‐called biologically inactive molecule,induces nitric oxide synthase in microglia via IL‐12Rβ1

Earlier we have demonstrated that IL‐12 p40 homodimer (p40₂) induces the expression of inducible nitric oxide synthase (iNOS) in microglia. This study was undertaken to investigate underlying mechanisms required for IL‐12 p40₂‐ and IL‐12 p70‐induced expression of iNOS in microglia. IL‐12 p40₂ alone induced the activation of both extracellular signal‐regulated kinase (ERK) and p38 mitogen‐activated protein kinase (MAPK). Interestingly, the ERK pathway coupled p40₂ to iNOS expression via C/EBPβ, but not NF‐κB, whereas the p38 pathway relayed the signal from p40₂ to iNOS expression via both NF‐κB and C/EBPβ. Furthermore, by using microglia from IL‐12Rβ1 (?/?) and IL‐12Rβ2 (?/?) mice or siRNA against IL‐12Rβ1 and IL‐12Rβ2, we demonstrate that p40₂ induced the expression of iNOS in microglia via IL‐12Rβ1–(ERK+p38)–(NF‐κB +C/EBPβ) pathway. In contrast, both IL‐12Rβ1 and IL‐12Rβ2 were involved for IL‐12 p70‐induced microglial expression of iNOS. Although IL‐12Rβ1 coupled p70 to NF‐κB and C/EBPβ, IL‐12Rβ2 was responsible for p70‐mediated activation of GAS. This study delineates a new role of IL‐12Rβ1 and IL‐12Rβ2 for the expression of iNOS and production of NO in microglia that may participate in the pathogenesis of neuroinflammatory diseases. © 2009 Wiley‐Liss, Inc.     

Short-term interleukin-1(beta) increases the release of secreted APP(alpha) via MEK1/2-dependent and JNK-dependent alpha-secretase cleavage in neuroglioma U251 cells

Several lines of neuroimmunological evidence correlate the development of the inflammatory responses of the brain with the formation of amyloid plaques associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Within this context, we tested the ability of interleukin-1beta (IL-1beta) to regulate the processing of beta-amyloid precursor protein (beta-APP) in neuroglioma U251 cells. Our findings have shown that short-term treatment with IL-1beta (2 hr) resulted in a concentration-dependent decrease in the amount of the cell-associated form of beta-APP in U251 cells as compared to untreated cells, whereas a 2-hr treatment with IL-1beta led to increased release of secreted APP(alpha) fragment (sAPP(alpha)) into the conditioned media of the cells. The fact that sAPP(alpha) is an alpha-secretase cleavage metabolite of the cell-associated form of beta-APP, and the observation that IL-1beta-induced sAPP(alpha) release could be blocked by tissue inhibitors of metalloproteinases-1 (alpha-secretase inhibitors), suggested that alpha-secretase might be involved in IL-1beta-induced-sAPP(alpha) release. Moreover, to determine whether an intracellular signaling pathway mediates the IL-1beta-induced increase in sAPP(alpha) secretion, we used various specific signaling inhibitors and found that sAPP(alpha) release is significantly blocked by the mitogen-activated protein kinase (MEK1/2) inhibitor PD98059 and the c-Jun N-terminal kinase inhibitor SP600125. These findings suggested that the mechanism of IL-1beta-induced-sAPP(alpha) release is dependent on MEK1/2- and JNK-activated alpha-secretase cleavage in neuroglioma U251 cells.     

GM-CSF and M-CSF modulate beta-chemokine and HIV-1 expression in microglia

Significant numbers of patients with acquired immunodeficiency syndrome (AIDS) develop CNS infection primarily in macrophages and microglial cells. Therefore, the regulation of human immunodeficiency virus type 1 (HIV-1) infection and activation of the brain mononuclear phagocytes subsequent to infection are important areas of investigation. In the current report, we studied the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) in the expression of antiviral beta-chemokines and HIV-1 p24 in cultures of primary human fetal microglia. We found that stimulation with GM-CSF or M-CSF induced macrophage inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented RANTES expression, after HIV-1 infection of microglia. This was not due to the effect of GM-CSF on viral expression because GM-CSF was neither necessary nor stimulatory for viral infection, nor did GM-CSF enhance the expression of env-pseudotyped reporter viruses. Blocking GM-CSF-induced microglial proliferation by nocodazole had no effect on beta-chemokine or p24 expression. The functional significance of the GM-CSF-induced beta-chemokines was suggested by the finding that, in the presence of GM-CSF, exogenous beta-chemokines lost their anti-HIV-1 effects. We further show that although HIV-1-infected microglia produced M-CSF, they failed to produce GM-CSF. In vivo, GM-CSF expression was localized to activated astrocytes and some inflammatory cells in HIV-1 encephalitis, suggesting paracrine activation of microglia through GM-CSF. Our results demonstrate a complex interplay between CSFs, chemokines, and virus in microglial cells and may have bearing on the interpretation of data derived in vivo and in vitro.     

Zaprinast, an inhibitor of cGMP-selective phosphodiesterases, enhances the secretion of TNF-alpha and IL-1beta and the expression of iNOS and MHC class II molecules in rat microglial cells

Proinflammatory cytokines produced by activated glial cells may in turn augment the immune/inflammatory reactions of glial cells through autocrine and paracrine routes. The NO/cGMP signaling represents one of the reactions of activated glial cells. We investigated whether the production of proinflammatory cytokines by glial cells is affected by NO-dependent downstream cGMP signaling. In primary cultures of mixed astrocytes and microglial cells, zaprinast (0.1 mM), an inhibitor of cGMP-selective phosphodiesterases, enhanced the basal and LPS (1.0 microg/ml)-induced secretion of TNF-alpha and IL-1beta. Zaprinast also enhanced NO production induced by LPS or IFN-gamma (100 U/ml), and in microglial cell cultures, but not in astrocyte cultures, zaprinast enhanced the basal and the IFN-gamma-induced production of the cytokines, TNF-alpha and IL-1beta, and of NO. This upregulation by zaprinast was partially inhibited by KT5823 (1.0 microM), an inhibitor of protein kinase G. The LPS-induced production of TNF-alpha, IL-1beta, and NO was inhibited by ODQ (50 microM), an inhibitor of soluble guanylyl cyclase, and by KT5823. Immunohistochemical analysis of mixed glial cell cultures showed that LPS/IFN-gamma-induced iNOS expression and the enhanced expression of iNOS by zaprinast were restricted to microglial cells. Zaprinast enhanced the IFN-gamma (200 U/ml)-induced expression of MHC Class II molecules in astrocytes and microglial cells in mixed cultures, but did not enhance this IFN-gamma-induced expression in pure astrocytes, which lacked paracrine TNF-alpha from microglial cells. Summarizing, zaprinast, which is associated with cGMP/protein kinase G signaling, may augment central immune/inflammatory reactions, possibly via the increased production of TNF-alpha and IL-1beta by activated microglial cells.     

C1q, the recognition subcomponent of the classical pathway of complement, drives microglial activation

Microglia, central nervous system (CNS) resident phagocytic cells, persistently police the integrity of CNS tissue and respond to any kind of damage or pathophysiological changes. These cells sense and rapidly respond to danger and inflammatory signals by changing their cell morphology; by release of cytokines, chemokines, or nitric oxide; and by changing their MHC expression profile. We have shown previously that microglial biosynthesis of the complement subcomponent C1q may serve as a reliable marker of microglial activation ranging from undetectable levels of C1q biosynthesis in resting microglia to abundant C1q expression in activated, nonramified microglia. In this study, we demonstrate that cultured microglial cells respond to extrinsic C1q with a marked intracellular Ca(2+) increase. A shift toward proinflammatory microglial activation is indicated by the release of interleukin-6, tumor necrosis factor-alpha, and nitric oxide and the oxidative burst in rat primary microglial cells, an activation and differentiation process similar to the proinflammatory response of microglia to exposure to lipopolysaccharide. Our findings indicate 1) that extrinsic plasma C1q is involved in the initiation of microglial activation in the course of CNS diseases with blood-brain barrier impairment and 2) that C1q synthesized and released by activated microglia is likely to contribute in an autocrine/paracrine way to maintain and balance microglial activation in the diseased CNS tissue.     

Pathogenic role of glial cells in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Alternatively, this glial response can also mediate a variety of deleterious events related to the production of pro-oxidant reactive species, and pro-inflammatory prostaglandin and cytokines. We discuss the potential protective and deleterious effects of glial cells in the SNpc of PD and examine how those factors may contribute to the pathogenesis of this disease.     

Interleukin-1beta upregulates functional expression of neurokinin-1 receptor (NK-1R) via NF-kappaB in astrocytes

Cytokines and neuropeptides are modulators of neuroimmunoregulation in the central nervous system (CNS). The interaction of these modulators may have important implications in CNS diseases. We investigated whether interleukin-1beta (IL-1beta) modulates the expression of neurokinin-1 receptor (NK-1R), the primary receptor for substance P (SP), a potent neuropeptide in the CNS. IL-1beta upregulated NK-1R expression in human astroglioma cells (U87 MG) and primary rat astrocytes at both mRNA and protein levels. IL-1beta treatment of U87 MG cells and primary rat astrocytes led to an increase in cytosolic Ca(2+) in response to SP stimulation, indicating that IL-1beta-induced NK-1R is functional. CP-96,345, a specific non-peptide NK-1R antagonist, inhibited SP-induced rise of [Ca(2+)](i) in the astroglioma cells. Investigation of the mechanism responsible for IL-1beta action revealed that IL-1beta has the ability of activating nuclear factor-kappab (NF-kappaB). Caffeic acid phenethyl ester (CAPE), a specific inhibitor of NF-kappaB activation, not only abrogated IL-1beta-induced NF-kappaB promoter activation, but also blocked IL-1beta-mediated induction of NK-1R gene expression. These findings provide additional evidence that there is a biological interaction between IL-1beta and the neuropeptide SP in the CNS, which may have important implications in the inflammatory diseases in the CNS.     

p38/SAPK2 controls gap junction closure in astrocytes

Astrocyte gap junction communication (GJC) is thought to contribute to death signal propagation following central nervous system injury, noteworthy in some ischemia/anoxia models. The inhibition of p38/stress-activated protein kinase 2 (p38/SAPK2) by a pyrimidyl imidazole derivative has been reported to reduce the extent of the lesion area after cerebral ischemia. Therefore, interleukin-1beta (IL-1beta), which contributes to stroke-induced brain injury and activates p38/SAPK2, and hyperosmolarity induced by sorbitol, a potent stimulus of p38/SAPK2 in non-neuronal cells, were used to investigate a possible involvement of p38/SAPK2 in GJC modulation in mouse cultured astrocytes. Both stimuli inhibited dye coupling within minutes. The IL-1beta effect was transient, while that of sorbitol lasted up to 90 min. Both stimuli induced a rapid p38/SAPK2 activation, the kinetic of which matched that of induction of dye coupling inhibition. Immunocytochemical studies showed that IL-1beta and sorbitol induced a p38/SAPK2 translocation from the nucleus to the cytoplasm. The pharmacological agent SB203580 specifically blocked p38/SAPK2 activation, cytoplasmic translocation and reversed the IL-1beta and sorbitol-induced inhibition of GJC. Further characterization of the p38/SAPK2 mode of action on GJC, performed with sorbitol, revealed an increased phosphorylation of protein kinase C (PKC) substrates abolished by both PKC inhibitors and SB203580. Expression and serine phosphorylation of connexin 43, the main component of astrocyte gap junctions, were unchanged, suggesting the existence of additional intracellular signaling mechanisms modulating the channel gating. Altogether, these results demonstrate that p38/SAPK2 is a central mediator of IL-1beta and sorbitol inhibitory actions on GJC and establish PKC among the distal effectors of p38/SAPK2.     

Glutathione-S-transferase-1 and interleukin-1beta gene polymorphisms in Japanese patients with Parkinson's disease.

We studied genetic polymorphisms in the glutathione-S-transferase-1 (GST-1) gene region and the interleukin-1beta (IL-1beta) promoter region in patients with Parkinson's disease (PD, n = 361), as well as controls (n = 257). Although we have confirmed the previous results, in a larger sample, that the IL-1beta genotype has affected the age at onset of PD patients, no contribution of the GST-1 gene polymorphism was observed in the allele frequency or the onset age of the disease in Japanese persons.     

CD38 regulation in activated astrocytes: Implications for neuroinflammation and HIV‐1 brain infection

Reactive astrogliosis is a key pathological aspect of neuroinflammatory disorders including human immunodeficiency virus type 1 (HIV‐1)‐associated neurological disease. On the basis of previous data that showedastrocytes activated with interleukin (IL)‐1β induce neuronal injury, we analyzed global gene changes in IL‐1β‐activated human astrocytes by gene microarray. Among the up‐regulated genes, CD38, a 45‐kDa type II single chain transmembrane glycoprotein, was a top candidate, with a 17.24‐fold change that was validated by real‐time polymerase chain reaction. Key functions of CD38 include enzymatic activities and involvement in adhesion and cell signaling. Importantly, CD38⁺CD8⁺ T‐cell expression is a clinical correlate for progression of HIV‐1 infection and biological marker for immune activation. Thus, CD38 expression in HIV‐1 and/or IL‐1β‐stimulated human astrocytes and human brain tissues was analyzed. IL‐1β and HIV‐1 activation of astrocytes enhanced CD38 mRNA levels. Both CD38 immunoreactivity and adenosine 5′‐diphosphate (ADP)‐ribosyl cyclase activity were up‐regulated in IL‐1β‐activated astrocytes. CD38 knockdown using specific siRNAs significantly reduced astrocyte proinflammatory cytokine and chemokine production. However, CD38 mRNA levels were unchanged in IL‐1β knockdown conditions, suggesting that IL‐1β autocrine loop is not implicated in this process. Quantitative immunohistochemical analysis of HIV‐seropositive without encephalitis and HIV‐1 encephalitis brain tissues showed significant up‐regulation of CD38, which colocalized with glial fibrillary acidic protein–positive cells in areas of inflammation. These results suggest an important role of CD38 in the regulation of astrocyte dysfunction during the neuroinflammatory processes involved in neurodegenerative/neuroinflammatory disorders such as HIV‐1 encephalitis. © 2009 Wiley‐Liss, Inc.     

The cytokine IL-1beta transiently enhances P2X7 receptor expression and function in human astrocytes

Extracellular nucleotide di- and triphosphates such as ATP and ADP mediate their effects through purinergic P2 receptors belonging to either the metabotropic P2Y or the ionotropic P2X receptor family. The P2X7R is a unique member of the P2X family, which forms a pore in response to ligand stimulation, regulating cell permeability, cytokine release, and/or apoptosis. This receptor is also unique in that its affinity for the ligand benzoyl-benzoyl ATP (BzATP) is at least 10-fold greater than that of ATP. Primary human fetal astrocytes in culture express low-levels of P2X7R mRNA and protein, and BzATP induces only a slight influx in intracellular calcium [Ca2+]i, with little demonstrable effect on gene expression or pore formation in these cells. We now show that, following treatment with the proinflammatory cytokine IL-1beta, BzATP induces a robust rise in [Ca2+]i with agonist and antagonist profiles indicative of the P2X7R. IL-1beta also induced the formation of membrane pores as evidenced by the uptake of YO-PRO-1 (375 Da). Quantitative real-time PCR demonstrated transient upregulation of P2X7R mRNA in IL-1beta-treated cells, while FACS analysis indicated a similar upregulation of P2X7R protein at the cell membrane. In multiple sclerosis lesions, immunoreactivity for the P2X7R was demonstrated on reactive astrocytes in autopsy brain tissues. In turn, P2X7R stimulation increased the production of IL-1-induced nitric oxide synthase activity by astrocytes in culture. These studies suggest that signaling via the P2X7R may modulate the astrocytic response to inflammation in the human central nervous system.     

IL‐1β induces hypomyelination in the periventricular white matter through inhibition of oligodendrocyte progenitor cell maturation via FYN/MEK/ERK signaling pathway in septic neonatal rats

Neuroinflammation elicited by microglia plays a key role in periventricular white matter (PWM) damage (PWMD) induced by infectious exposure. This study aimed to determine if microglia‐derived interleukin‐1β (IL‐1β) would induce hypomyelination through suppression of maturation of oligodendrocyte progenitor cells (OPCs) in the developing PWM. Sprague‐Dawley rats (1‐day old) were injected with lipopolysaccharide (LPS) (1 mg/kg) intraperitoneally, following which upregulated expression of IL‐1β and IL‐1 receptor 1 (IL‐1R₁) was observed. This was coupled with enhanced apoptosis and suppressed proliferation of OPCs in the PWM. The number of PDGFR‐α and NG2‐positive OPCs was significantly decreased in the PWM at 24 h and 3 days after injection of LPS, whereas it was increased at 14 days and 28 days. The protein expression of Olig1, Olig2, and Nkx2.2 was significantly reduced, and mRNA expression of Tcf4 and Axin2 was upregulated in the developing PWM after LPS injection. The expression of myelin basic protein (MBP) and 2',3'‐cyclic‐nucleotide 3"‐phosphodiesterase (CNPase) was downregulated in the PWM at 14 days and 28 days after LPS injection; this was linked to reduction of the proportion of myelinated axons and thinner myelin sheath as revealed by electron microscopy. Primary cultured OPCs treated with IL‐1β showed the failure of maturation and proliferation. Furthermore, FYN/MEK/ERK signaling pathway was involved in suppression of maturation of primary OPCs induced by IL‐1β administration. Our results suggest that following LPS injection, microglia are activated and produce IL‐1β in the PWM in the neonatal rats. Excess IL‐1β inhibits the maturation of OPCs via suppression of FYN/MEK/ERK phosphorylation thereby leading to axonal hypomyelination. GLIA 2016;64:583–602