Oxidative Burst of Circulating Neutrophils Following Traumatic Brain Injury in Human

Besides secondary injury at the lesional site, Traumatic brain injury (TBI) can cause a systemic inflammatory response, which may cause damage to initially unaffected organs and potentially further exacerbate the original injury. Here we investigated plasma levels of important inflammatory mediators, oxidative activity of circulating leukocytes, particularly focusing on neutrophils, from TBI subjects and control subjects with general trauma from 6 hours to 2 weeks following injury, comparing with values from uninjured subjects. We observed increased plasma level of inflammatory cytokines/molecules TNF-α, IL-6 and CRP, dramatically increased circulating leukocyte counts and elevated expression of TNF-α and iNOS in circulating leukocytes from TBI patients, which suggests a systemic inflammatory response following TBI. Our data further showed increased free radical production in leukocyte homogenates and elevated expression of key oxidative enzymes iNOS, COX-2 and NADPH oxidase (gp91^phox) in circulating leukocytes, indicating an intense induction of oxidative burst following TBI, which is significantly greater than that in control subjects with general trauma. Furthermore, flow cytometry assay proved neutrophils as the largest population in circulation after TBI and showed significantly up-regulated oxidative activity and suppressed phagocytosis rate for circulating neutrophils following brain trauma. It suggests that the highly activated neutrophils might play an important role in the secondary damage, even outside the injured brain. Taken together, the potent systemic inflammatory response induced by TBI, especially the intensively increase oxidative activity of circulating leukocytes, mainly neutrophils, may lead to a systemic damage, dysfunction/damage of bystander tissues/organs and even further exacerbate secondary local damage. Controlling these pathophysiological processes may be a promising therapeutic strategy and will protect unaffected organs and the injured brain from the secondary damage.     

Neuroinflammation and Memory: The Role of Prostaglandins

Neuroinflammation is a complex response to brain injury involving the activation of glia, release of inflammatory mediators within the brain, and recruitment of peripheral immune cells. Interestingly, memory deficits have been observed following many inflammatory states including infection, traumatic brain injury (TBI), normal aging, and Alzheimer’s disease (AD). Prostaglandins (PGs), a class of lipid mediators which can have inflammatory actions, are upregulated by these inflammatory challenges and can impair memory. In this paper, we critically review the success of nonsteroidal anti-inflammatory drugs, which prevent the formation of PGs, in preventing neuroinflammation-induced memory deficits following lipopolysaccharide injection, TBI, aging, and experimental models of AD in rodents and propose a mechanism by which PGs could disrupt memory formation.     

Call Off the Dog(ma): M1/M2 Polarization Is Concurrent following Traumatic Brain Injury

Following the primary mechanical impact, traumatic brain injury (TBI) induces the simultaneous production of a variety of pro- and anti-inflammatory molecular mediators. Given the variety of cell types and their requisite expression of cognate receptors this creates a highly complex inflammatory milieu. Increasingly in neurotrauma research there has been an effort to define injury-induced inflammatory responses within the context of in vitro defined macrophage polarization phenotypes, known as “M1” and “M2”. Herein, we expand upon our previous work in a rodent model of TBI to show that the categorization of inflammatory response cannot be so easily delineated using this nomenclature. Specifically, we show that TBI elicited a wide spectrum of concurrent expression responses within both pro- and anti-inflammatory arms. Moreover, we show that the cells principally responsible for the production of these inflammatory mediators, microglia/macrophages, simultaneously express both “M1” and “M2” phenotypic markers. Overall, these data align with recent reports suggesting that microglia/macrophages cannot adequately switch to a polarized “M1-only” or “M2-only” phenotype, but display a mixed phenotype due to the complex signaling events surrounding them.     

Molecular mechanisms in the pathogenesis of traumatic brain injury

Traumatic brain injury (TBI) is a serious neurodisorder commonly caused by car accidents, sports related events or violence. Preventive measures are highly recommended to reduce the risk and number of TBI cases. The primary injury to the brain initiates a secondary injury process that spreads via multiple molecular mechanisms in the pathogenesis of TBI. The events leading to both neurodegeneration and functional recovery after TBI are generalized into four categories: (i) primary injury that disrupts brain tissues; (ii) secondary injury that causes pathophysiology in the brain; (iii) inflammatory response that adds to neurodegeneration; and (iv) repair-regeneration that may contribute to neuronal repair and regeneration to some extent following TBI. Destructive multiple mediators of the secondary injury process ultimately dominate over a few intrinsic protective measures, leading to activation of cysteine proteases such as calpain and caspase-3 that cleave key cellular substrates and cause cell death. Experimental studies in rodent models of TBI suggest that treatment with calpain inhibitors (e.g., AK295, SJA6017) and neurotrophic factors (e.g., NGF, BDNF) can prevent neuronal death and dysfunction in TBI. Currently, there is still no precise therapeutic strategy for the prevention of pathogenesis and neurodegeneration following TBI in humans. The search continues to explore new therapeutic targets and development of promising drugs for the treatment of TBI.     

The duality of the inflammatory response to traumatic brain injury

One and a half to two million people sustain a traumatic brain injury (TBI) in the US each year, of which approx 70,000–90,000 will suffer from long-term disability with dramatic impacts on their own and their families’ lives and enormous socio-economic costs. Brain damage following traumatic injury is a result of direct (immediate mechanical disruption of brain tissue, or primary injury) and indirect (secondary or delayed) mechanisms. These secondary mechanisms involve the initiation of an acute inflammatory response, including breakdown of the blood-brain barrier (BBB), edema formation and swelling, infiltration of peripheral blood cells and activation of resident immunocompetent cells, as well as the intrathecal release of numerous immune mediators such as interleukins and chemotactic factors. An overview over the inflammatory response to trauma as observed in clinical and in experimental TBI is presented in this review. The possibly harmful/beneficial sequelae of post-traumatic inflammation in the central nervous system (CNS) are discussed using three model mediators of inflammation in the brain, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β). While the former two may act as important mediators for the initiation and the support of post-traumatic inflammation, thus causing additional cell death and neurologic dysfunction, they may also pave the way for reparative processes. TGF-β, on the other hand, is a potent anti-inflammatory agent, which may also have some deleterious long-term effects in the injured brain. The implications of this duality of the post-traumatic inflammatory response for the treatment of brain-injured patients using anti-inflammatory strategies are discussed.     

Different inflammatory mediators induce inflammation and pain after application of liquid nitrogen to the skin

The application of liquid nitrogen to the skin induces inflammation and pain. However, there is little data on the role of inflammatory mediators in the production of these symptoms. We have developed an experimental model to study some aspects of the inflammatory response and its mediators following the application of cold. We have applied liquid nitrogen jets to subcutaneous air pouches in the dorsal skin of rats to study the kinetics of the migration of inflammatory cells; also to the ear for histopathological analysis and on the paws for edema and pain. Inflammatory mediators were identified by pharmacological means. The results showed that the cellular inflammatory response was characterized by persistent cell migration, mainly of granulocytes. Histopathology of the ears confirmed these findings. Histamine and sympathomimetic mediators were mainly responsible for the resultant swelling. However, the hypernociception that resulted involved other mediators including IL-1 and eicosanoids. These data suggest that interference with the release of inflammatory mediators might reduce the side effects of cryosurgery and prevent hyperalgesia and inflammation at the site of application of cold.     

Different inflammatory mediators induce inflammation and pain after application of liquid nitrogen to the skin

The application of liquid nitrogen to the skin induces inflammation and pain. However, there is little data on the role of inflammatory mediators in the production of these symptoms. We have developed an experimental model to study some aspects of the inflammatory response and its mediators following the application of cold. We have applied liquid nitrogen jets to subcutaneous air pouches in the dorsal skin of rats to study the kinetics of the migration of inflammatory cells; also to the ear for histopathological analysis and on the paws for edema and pain. Inflammatory mediators were identified by pharmacological means. The results showed that the cellular inflammatory response was characterized by persistent cell migration, mainly of granulocytes. Histopathology of the ears confirmed these findings. Histamine and sympathomimetic mediators were mainly responsible for the resultant swelling. However, the hypernociception that resulted involved other mediators including IL-1 and eicosanoids. These data suggest that interference with the release of inflammatory mediators might reduce the side effects of cryosurgery and prevent hyperalgesia and inflammation at the site of application of cold.     

Elevated Cerebral Cortical CD24 Levels in Patients and Mice with Traumatic Brain Injury: A Potential Negative Role in Nuclear Factor Kappa B/Inflammatory Factor Pathway

Increasing evidence indicates that sterile inflammatory response contributes to secondary brain injury following traumatic brain injury (TBI). However, the specific mechanisms remain largely unknown, as is whether CD24, known as an important regulator in the non-infectious inflammatory response, plays a role in secondary brain injury after TBI. Here, the expression of CD24 was detected in samples from patients with TBI by quantitative real-time polymerase chain reaction (PCR), western blotting, immunohistochemistry and immunofluorescence. RNA interference was used to investigate the effects of CD24 on inflammatory response in a mouse model of TBI. Nuclear factor kappa B (NF-κB) DNA-binding activity was measured by electrophoretic mobility shift assay, and the levels of downstream pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and Interleukin 1β (IL-1β) were detected by real-time PCR. The results indicated that both the mRNA and protein levels of CD24 were markedly elevated after TBI in humans and mice, showing a time-dependent expression. The expression of CD24 could be observed in neurons, astrocytes and microglia in both humans and mice. Meanwhile, downregulation of CD24 significantly induced an increase of NF-κB DNA-binding activity and mRNA levels of TNF-α and IL-1β. These findings indicated that CD24 expression could negatively regulate the NF-κB/inflammatory factor pathway after experimental TBI in mice, thus providing a novel target for therapeutic intervention of TBI.     

Glutamate Release and Free Radical Production Following Brain Injury: Effects of Posttraumatic Hypothermia

Abstract: Posttraumatic hypothermia reduces the extent of neuronal damage in remote cortical and subcortical structures following traumatic brain injury (TBI). We evaluated whether excessive extracellular release of glutamate and generation of hydroxyl radicals are associated with remote traumatic injury, and whether posttraumatic hypothermia modulates these processes. Lateral fluid percussion was used to induce TBI in rats. The salicylate-trapping method was used in conjunction with microdialysis and HPLC to detect hydroxyl radicals by measurement of the stable adducts 2,3- and 2,5-dihydroxybenzoic acid (DHBA). Extracellular glutamate was measured from the same samples. Following trauma, brain temperature was maintained for 3 h at either 37 or 30°C. Sham-trauma animals were treated in an identical manner. In the normothermic group, TBI induced significant elevations in 2,3-DHBA (3.3-fold, p < 0.01), 2,5-DHBA (2.5-fold, p < 0.01), and glutamate (2.8-fold, p < 0.01) compared with controls. The levels of 2,3-DHBA and glutamate remained high for approximately 1 h after trauma, whereas levels of 2,5-DHBA remained high for the entire sampling period (4 h). Linear regression analysis revealed a significant positive correlation between integrated 2,3-DHBA and glutamate concentrations ( p < 0.05). Posttraumatic hypothermia resulted in suppression of both 2,3- and 2,5-DHBA elevations and glutamate release. The present data indicate that TBI is followed by prompt increases in both glutamate release and hydroxyl radical production from cortical regions adjacent to the impact site. The magnitude of glutamate release is correlated with the extent of the hydroxyl radical adduct, raising the possibility that the two responses are associated. Posttraumatic hypothermia blunts both responses, suggesting a mechanism by which hypothermia confers protection following TBI.     

Berberine Protects against Neuronal Damage via Suppression of Glia-Mediated Inflammation in Traumatic Brain Injury

Traumatic brain injury (TBI) triggers a series of neuroinflammatory processes that contribute to evolution of neuronal injury. The present study investigated the neuroprotective effects and anti-inflammatory actions of berberine, an isoquinoline alkaloid, in both in vitro and in vivo TBI models. Mice subjected to controlled cortical impact injury were injected with berberine (10 mg·kg⁻¹) or vehicle 10 min after injury. In addition to behavioral studies and histology analysis, blood-brain barrier (BBB) permeability and brain water content were determined. Expression of PI3K/Akt and Erk signaling and inflammatory mediators were also analyzed. The protective effect of berberine was also investigated in cultured neurons either subjected to stretch injury or exposed to conditioned media with activated microglia. Berberine significantly attenuated functional deficits and brain damage associated with TBI up to day 28 post-injury. Berberine also reduced neuronal death, apoptosis, BBB permeability, and brain edema at day 1 post-injury. These changes coincided with a marked reduction in leukocyte infiltration, microglial activation, matrix metalloproteinase-9 activity, and expression of inflammatory mediators. Berberine had no effect on Akt or Erk 1/2 phosphorylation. In mixed glial cultures, berberine reduced TLR4/MyD88/NF-κB signaling. Berberine also attenuated neuronal death induced by microglial conditioned media; however, it did not directly protect cultured neurons subjected to stretch injury. Moreover, administration of berberine at 3 h post-injury also reduced TBI-induced neuronal damage, apoptosis and inflammation in vivo. Berberine reduces TBI-induced brain damage by limiting the production of inflammatory mediators by glial cells, rather than by a direct neuroprotective effect.     

Wogonin improves histological and functional outcomes, and reduces activation of TLR4/NF-κB signaling after experimental traumatic brain injury

Background

Traumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to neuronal damage and behavioral impairment. This study was undertaken to investigate the effects of wogonin, a flavonoid with potent anti-inflammatory properties, on functional and histological outcomes, brain edema, and toll-like receptor 4 (TLR4)- and nuclear factor kappa B (NF-κB)-related signaling pathways in mice following TBI.

Methodology/Principal Findings

Mice subjected to controlled cortical impact injury were injected with wogonin (20, 40, or 50 mg·kg⁻¹) or vehicle 10 min after injury. Behavioral studies, histology analysis, and measurement of blood-brain barrier (BBB) permeability and brain water content were carried out to assess the effects of wogonin. Levels of TLR4/NF-κB-related inflammatory mediators were also examined. Treatment with 40 mg·kg⁻¹ wogonin significantly improved functional recovery and reduced contusion volumes up to post-injury day 28. Wogonin also significantly reduced neuronal death, BBB permeability, and brain edema beginning at day 1. These changes were associated with a marked reduction in leukocyte infiltration, microglial activation, TLR4 expression, NF-κB translocation to nucleus and its DNA binding activity, matrix metalloproteinase-9 activity, and expression of inflammatory mediators, including interleukin-1β, interleukin-6, macrophage inflammatory protein-2, and cyclooxygenase-2.

Conclusions/Significance

Our results show that post-injury wogonin treatment improved long-term functional and histological outcomes, reduced brain edema, and attenuated the TLR4/NF-κB-mediated inflammatory response in mouse TBI. The neuroprotective effects of wogonin may be related to modulation of the TLR4/NF-κB signaling pathway.     

Toll-Like Receptor 4 Knockdown Attenuates Brain Damage and Neuroinflammation After Traumatic Brain Injury via Inhibiting Neuronal Autophagy and Astrocyte Activation

Toll-like receptor 4 (TLR4) has been linked to various pathophysiological conditions, such as traumatic brain injury (TBI). It is reported that posttraumatic neuroinflammation is an essential event in the progression of brain injury after TBI. Recent evidences indicate that TLR4 mediates glial phagocytic activity and inflammatory cytokines production. Thus, TLR4 may be an important therapeutic target for neuroinflammatory injury post-TBI. This study was designed to explore potential effects and underlying mechanisms of TLR4 in rats suffered from TBI. TBI model was induced using a controlled cortical impact in rats, and application of TLR4 shRNA silenced TLR4 expression in brain prior to TBI induction. Elevated TLR4 was specifically observed in the hippocampal astrocytes and neurons posttrauma. Interestingly, TLR4 shRNA decreased the concentrations of interleukin (IL)-1β, IL-6, and tissue necrosis factor-α; alleviated hippocampal neuronal damage; reduced brain edema formation; and improved neurological deficits after TBI. Meanwhile, to further explore underlying molecular mechanisms of this neuroprotective effects of TLR4 knockdown, our results showed that TLR4 knockdown significantly inhibited the upregulation of autophagy-associated proteins caused by TBI. More importantly, an autophagy inducer, rapamycin pretreated, could partially abolish neuroprotective effects of TLR4 knockdown on TBI rats. Furthermore, TLR4 silencing markedly suppressed GFAP upregulation and improved cell hypertrophy to attenuate TBI-induced astrocyte activation. Taken together, these findings suggested that TLR4 knockdown ameliorated neuroinflammatory response and brain injury after TBI through suppressing autophagy induction and astrocyte activation.     

大鼠颅脑损伤后差异表达基因及miRNA研究

研究背景创伤性脑损伤(Traumatic brain injury, TBI)是致死率和致残率极高的外科疾患,我国在对于TBI的判断、治疗等方面还处于薄弱阶段,因此我们需要在分子层面了解大鼠颅脑损伤后基因及miRNA表达差异,以便更好地对症治疗。目的了解大鼠颅脑损伤后基因及miRNA表达差异,为临床治疗TBI提供新的思路。方法利用GEO2R筛选基因,然后用MiRwalk软件对筛选的miRNA的靶基因进行预测,再用DAVID做基因本体论功能富集分析,最后利用cytoscape做网络关系图。结果发现247个相对明显的差异表达的基因,包括150个上调表达基因和97个下调表达基因;7个差异表达的miRNA,包括2个上调表达miRNA和5个下调表达miRNA。这些差异表达基因在细胞内和细胞外都起作用,并且在炎症反应,药物应答等生物过程中起作用。将差异基因与靶基因对比后,可得到48个重合基因,同时发现这些重合基因与差异表达的miRNA有着一定的联系。     

FTY720 attenuates accumulation of EMAP-II+ and MHC-II+ monocytes in early lesions of rat traumatic brain injury

FTY720 (Fingolimod) is a novel type of immunosuppressive agent inhibiting lymphocyte egress from secondary lymphoid tissues thereby causing peripheral lymphopenia. FTY720 can inhibit macrophage infiltration into inflammatory lesions under pathological conditions. FTY720 has been clinically evaluated for prophylaxis of allograft rejection and treatment of multiple sclerosis, showing promising immunosuppressive effects. A robust inflammatory response after traumatic brain injury (TBI) plays an important role in the secondary or delayed injuries of TBI. Here we have investigated by immunohistochemistry in a rat TBI model the effects of FTY720 on early cell accumulation into the inflammatory tissue response and on expression of major histo-compatibility complex class II (MHC-II) and endothelial-monocyte activating polypeptide II (EMAP-II). Accumulation of MHC-II(+) or EMAP-II(+) cells became significant 1 day after injury and continuously increased during the early time periods. Further, double-staining experiments confirmed that the major cellular sources of MHC-II were reactive macrophages, however MHC-II(+) cells only constituted a small subpopulation of reactive macrophages. Immediately after TBI, peripheral administration of FTY720 (1 mg/kg in 1 mL saline, every second day) significantly attenuated the accumulation of MHC-II(+) macrophages from Day 1 to 4 and significantly attenuated the accumulation of EMAP-II(+) macrophages/microglia at Day 4. Our findings show that FTY720 attenuates early accumulation of EMAP-II(+) and MHC-II(+) reactive monocytes following TBI, indicating that FTY720 might be a drug candidate to inhibit brain inflammatory reaction following TBI.     

创伤性脑损伤中神经炎症相关细胞的研究进展

创伤性脑损伤(traumatic brain injury, TBI), 亦称颅脑损伤或头部外伤, 专指由外伤引起的脑组织损害。然而,从轻度到重度的TBI,改善TBI患者预后的治疗方法都十分匮乏。神经炎症可引起脑外伤后急性继发性损伤,并与慢性神经退行性疾病有关,因此,系统了解参与TBI后神经炎性反应的细胞显得尤为重要。主要对TBI中参与炎症反应的细胞（如小胶质细胞、星形胶质细胞、少突细胞、中性粒细胞和淋巴细胞）的启动以及相互作用的最新研究进展进行了综述,以期为临床研究提供新的策略。     

Opposing roles for reactive astrocytes following traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Current medical therapies exhibit limited efficacy in reducing neurological injury and the prognosis for patients remains poor. While most research is focused on the direct protection of neuronal cells, non-neuronal cells, such as astrocytes, may exert an active role in the pathogenesis of TBI. Astrocytes, the predominant cell type in the human brain, are traditionally associated with providing only structural support within the CNS. However, recent work suggests astrocytes may regulate brain homeostasis and limit brain injury. In contrast, reactive astrocytes may also contribute to increased neuroinflammation, the development of cerebral edema, and elevated intracranial pressure, suggesting possible roles in exacerbating secondary brain injury following neurotrauma. The multiple, opposing roles for astrocytes following neurotrauma may have important implications for the design of directed therapeutics to limit neurological injury. As such, a primary focus of this review is to summarize the emerging evidence suggesting reactive astrocytes influence the response of the brain to TBI.     

Modulation of autophagy in traumatic brain injury

Traumatic brain injury (TBI) is defined as a traumatically induced structural injury or physiological disruption of brain function as a result of external forces, leading to adult disability and death. A growing body of evidence reveals that alterations in autophagy-related proteins exist extensively in both experimentally and clinically after TBI. Of note, the autophagy pathway plays an essential role in pathophysiological processes, such as oxidative stress, inflammatory response, and apoptosis, thus contributing to neurological properties of TBI. With this in mind, this review summarizes a comprehensive overview on the beneficial and detrimental effects of autophagy in pathophysiological conditions and how these activities are linked to the pathogenesis of TBI. Moreover, the relationship between oxidative stress, inflammation, apoptosis, and autophagy occur TBI. Ultimately, multiple compounds and various drugs targeting the autophagy pathway are well described in TBI. Therefore, autophagy flux represents a potential clinical therapeutic value for the treatment of TBI and its complications.     

Activation of bradykinin B2 receptor induced the inflammatory responses of cytosolic phospholipase A2 after the early traumatic brain injury

Phospholipase A₂ is a known aggravator of inflammation and deteriorates neurological outcomes after traumatic brain injury (TBI), however the exact inflammatory mechanisms remain unknown. This study investigated the role of bradykinin and its receptor, which are known initial mediators within inflammation activation, as well as the mechanisms of the cytosolic phospholipase A₂ (cPLA₂)-related inflammatory responses after TBI. We found that cPLA₂ and bradykinin B2 receptor were upregulated after a TBI. Rats treated with the bradykinin B2 receptor inhibitor LF 16-0687 exhibited significantly less cPLA₂ expression and related inflammatory responses in the brain cortex after sustaining a controlled cortical impact (CCI) injury. Both the cPLA₂ inhibitor and the LF16-0687 improved CCI rat outcomes by decreasing neuron death and reducing brain edema. The following TBI model utilized both primary astrocytes and primary neurons in order to gain further understanding of the inflammation mechanisms of the B2 bradykinin receptor and the cPLA₂ in the central nervous system. There was a stronger reaction from the astrocytes as well as a protective effect of LF16-0687 after the stretch injury and bradykinin treatment. The protein kinase C pathway was thought to be involved in the B2 bradykinin receptor as well as the cPLA₂-related inflammatory responses. Rottlerin, a Protein Kinase C (PKC) δ inhibitor, decreased the activity of the cPLA₂ activity post-injury, and LF16-0687 suppressed both the PKC pathway and the cPLA₂ activity within the astrocytes. These results indicated that the bradykinin B2 receptor-mediated pathway is involved in the cPLA₂-related inflammatory response from the PKC pathway.     

Sigma-1 Receptor Modulates Neuroinflammation After Traumatic Brain Injury

Traumatic brain injury (TBI) remains a significant clinical problem and contributes to one-third of all injury-related deaths. Activated microglia-mediated inflammatory response is a distinct characteristic underlying pathophysiology of TBI. Here, we evaluated the effect and possible mechanisms of the selective Sigma-1 receptor agonist 2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate (PRE-084) in mice TBI model. A single intraperitoneal injection 10 μg/g PRE-084, given 15 min after TBI significantly reduced lesion volume, lessened brain edema, attenuated modified neurological severity score, increased the latency time in wire hang test, and accelerated body weight recovery. Moreover, immunohistochemical analysis with Iba1 staining showed that PRE-084 lessened microglia activation. Meanwhile, PRE-084 reduced nitrosative and oxidative stress to proteins. Thus, Sigma-1 receptors play a major role in inflammatory response after TBI and may serve as useful target for TBI treatment in the future.     

Bmx regulates LPS-induced IL-6 and VEGF production via mRNA stability in rheumatoid synovial fibroblasts

Discordant cytokine production is characteristic of chronic inflammatory conditions like rheumatoid arthritis (RA), and anti-cytokine therapeutics are becoming routinely used to treat RA in the clinic. Fibroblasts from rheumatoid synovium have been shown to contribute to cytokine production in inflamed joints; likewise these cells also produce cytokines in response to inflammatory mediators signalling through Toll like receptors (TLRs). Tyrosine kinase activity is essential to LPS-induced cytokine production, and we have previously implicated a role for the Tec kinase, Bmx, in inflammatory cytokine production. Here we show that Bmx kinase activity in RASF is increased following LPS stimulation and that Bmx is involved in the regulation of LPS-induced IL-6 and VEGF production via mRNA stabilisation. This is an important insight into the regulation of VEGF, which is involved in a wide range of different pathologies, and may lead to more effective design of novel anti-inflammatory/angiogenic therapeutics for conditions such as RA.