Inflammation & Allergy-Drug Targets (Discontinued) - Volume 6, Issue 3, 2007

Classically, B-lymphocytes (B cells) are considered to be the mediators of humoral immunity and their role in inflammatory disease largely confined to the down-stream function of antigen-antibody complexes, e.g., in fixing complement and mediating antibody dependent cellular cytotoxicity. More recently, and with the growing acceptance of the view that the immune system operates as an interconnected web of cells and cytokines, a larger role for B cells has been proposed. In this review, with a focus on how B cells and their cytokine products may present novel therapeutic targets, we will briefly discuss B cell ontogeny and discuss the evidence supporting a larger role for B cells in a variety of inflammatory diseases. Special emphasis will be placed on autoimmune diseases. These discussions are intended to provide the reader with the basis for viewing B cells as players of a broader role in inflammatory disease and thus suggest avenues for exploiting B cell directed therapy in novel ways.

Asthma is a chronic inflammatory disease of the airways which affects about 10-25% of children in Western countries. Monitoring of inflammation is considered an important tool in the diagnosis and follow-up of asthma, including assessment of severity and response to treatment. Bronchial biopsy specimens and bronchoalveolar lavage are reliable ways to assess airway inflammation. However, such invasive procedures are not feasible for repetitive measurements. In clinical practice, correlation of symptom scores and measurement of lung function with airway inflammation may be poor. Bronchial hyperresponsiveness to metacholine and induced sputum are time-consuming, difficult to perform before adolescence and can not be measured serially. Therefore, the greatest interest has recently been directed towards alternative approaches to determine markers involved in the inflammatory reaction. In childhood, such approaches must be noninvasive, reproducible and easy to perform. Furthermore, the inflammatory markers should accurately measure not only the degree of inflammation but also changes depending upon treatment or allergen exposure. Recently, the measurements of inflammatory markers in both exhaled breath and condensate have emerged as a possible non invasive method in the assessment of airway inflammation.

Cytokines mediate communication between cells of the immune system and are of crucial importance to induce an appropriately regulated immune response to invading pathogens. Cytokine receptor signaling has to be tightly controlled to balance anti-microbial and tissue-destructive effects, both of which are inherently associated with cytokinemediated inflammation. Suppressor of cytokine signaling (SOCS) proteins have been identified as intracellular, inducible feedback inhibitors which limit the signal magnitude of cytokines employing Janus kinase (Jak) and signal transducer and activator of transcription (STAT) pathways. Interfering with cytokine receptor signaling has been shown to be a promising strategy used by various microbial pathogens to evade otherwise detrimental immune responses. To this, microbes make use of a variety of different means. Recent reports now indicate that certain bacteria, viruses and parasites have also learned to use the host's inhibitory SOCS proteins for manipulating cytokine receptor signaling, especially to circumvent the actions of interferon. Progress in the field of microbial immune evasion mediated by SOCS proteins is discussed in this review. Modulating the host's SOCS system therefore could also be a promising new approach for molecular therapeutic strategies.

Resveratrol (trans-3,4',5-trihydroxystilbene), a natural polyphenolic, non-flavonoid antioxidant, is a phytoalexin found in many plants including grapes, nuts and berries. Recent studies have documented that resveratrol has various health benefits, such as cardiovascular and cancer preventive properties. However, the experimental basis for such health benefit is not fully understood. One of the possible mechanisms for its protective activities is by down regulation of the inflammatory responses. That includes the inhibition of synthesis and release of pro-inflammatory mediators, modifications of eicosanoid synthesis, inhibition of some activated immune cells, or inhibiting the enzymes, such as cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2), which are responsible for the synthesis of pro-inflammatory mediators through the inhibitory effect of resveratrol on transcription factors like nuclear factor κB (NFκB) or activator protein-1 (AP-1). Being a phenolic compound, resveratrol certainly possesses a low bioavailability and most importantly, a rapid clearance from the plasma. Recent growing interest in varying protective nature of resveratrol may clinically also hold a respectable position as a better alternative for anti-inflammatory drugs. The purpose of this review is to provide evidence that resveratrol exhibits potent anti-inflammatory activity and also to explain the underling mechanism for both resveratrol- induced cardioprotective and anti-inflammatory properties. While it is true that the cardioprotective properties of resveratrol are likely attributable, at least in part, to its anti-inflammatory properties, the mechanisms discussed address foremost mechanisms for the anti-inflammatory activity which, in turn, is responsible for cardioprotection.

Dehydroepiandrosterone (DHEA) has a protective role against atherosclerosis, most likely mediating an antiinflammatory action. In order to understand the mechanisms involved in this protection, we evaluated the effects of DHEA on several molecules involved in the inflammatory response. Reactive oxygen species (ROS), expression of adhesion molecules, activation of the NF-κB/IκB-α pathway and of the AP-1 transcription factor were evaluated in human umbilical vein endothelial cells (HUVECs) treated with oxidized low density lipoproteins (oxLDL) and DHEA. We also determined if DHEA affected LDL oxidation in vitro. 100 μM DHEA-treatment inhibited the oxLDL-induced expression of ICAM-1, VCAM-1, PECAM-1, ROS production, and U937 cells adhesion to HUVECs. DHEA also delayed the kinetics of LDL oxidation in vitro. While DHEA did not affect the translocation of NF-κB neither the degradation IκB-α, it led to an increased translocation of AP-1. Our results suggest that DHEA inhibits the expression of molecules involved in the inflammatory process in endothelial cells activated with oxLDL, therefore its potential anti-inflammatory properties should be evaluated for the treatment of chronic inflammatory diseases such as atherosclerosis.

Macrophage migration inhibitory factor (MIF), a cytokine originally reported in the 1960s as the prototypic T lymphokine, has emerged in recent years as a key factor regulating inflammatory responses. Both by directly activating immune cells, and by participating in activation entrained by other stimuli, MIF is important in innate and adaptive immune responses as well as tissue-specific mechanisms of damage. As a consequence of its involvement in multiple stages of the immune-inflammatory response, MIF has the potential to be involved in the pathogenesis of a range of immunemediated inflammatory diseases affecting multiple organ systems. Diseases in which a role for MIF has been strongly validated include rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, asthma, inflammatory liver disease, and most recently systemic lupus erythematosus. Recent data have provided mechanisms of action for MIF which further support its suitability as a therapeutic target. Finally, MIF has a unique relationship with glucocorticoids, acting to counter-regulate their anti-inflammatory effects, such that MIF antagonist therapy may be a direct route to ‘steroid-sparing’. Methods of targeting MIF therapeutically have also emerged in recent years, based on the unique protein structure of MIF which affords opportunities for direct antagonism by small molecules, as well as by protein therapeutics such as monoclonal antibodies. Clinical trials of MIF antagonist therapies are likely before the end of the current decade.