Leukotriene B4 Synthesis In Neutrophils Research Articles

Distinct Mechanisms of Type 3 Secretion System Recognition Control LTB4 Synthesis in Neutrophils versus Macrophages.

Leukotriene B4 (LTB4) is critical for initiating the inflammatory cascade in response to infection. However, Yersinia pestis colonizes the host by inhibiting the timely synthesis of LTB4 and inflammation. Here, we show that the bacterial type 3 secretion system (T3SS) is the primary pathogen associated molecular pattern (PAMP) responsible for LTB4 production by leukocytes in response to Yersinia and Salmonella, but synthesis is inhibited by the Yop effectors during Yersinia interactions. Moreover, we unexpectedly discovered that T3SS-mediated LTB4 synthesis by neutrophils and macrophages require two distinct host signaling pathways. We show that the SKAP2/PLC signaling pathway is essential for LTB4 production by neutrophils but not macrophages. Instead, phagocytosis and the NLRP3/CASP1 inflammasome are needed for LTB4 synthesis by macrophages. Finally, while recognition of the T3SS is required for LTB4 production, we also discovered a second unrelated PAMP-mediated signal independently activates the MAP kinase pathway needed for LTB4 synthesis. Together, these data demonstrate significant differences in the signaling pathways required by macrophages and neutrophils to quickly respond to bacterial infections.

Petasites--Zeller: ZE 339.

The Swiss company Zeller is developing an extract of the plant Petasites hybridus (butterbur) as an antiallergic agent. Petasites hybridus extracts have been known for some time to have therapeutic properties. Zeller's extract is codenamed ZE 339. In in vitro studies, ZE 339 inhibited cysteinyl-leukotriene synthesis in eosinophils and leukotriene B4 synthesis in neutrophils. In mid-2003, ZE 339 was approved, and launched, in Switzerland as Tesalin for the treatment of seasonal allergic rhinitis as a prescription-only product. Tesalin is available as film-coated tablets. Zeller has stated that hepatotoxicity cannot be totally excluded as a possible adverse reaction to Tesalin.

Adenosine A2 receptor‐induced inhibition of leukotriene B4 synthesis in whole blood ex vivo

1. Engagement of adenosine A2 receptors suppresses several leukocyte functions. In the present study, we examined the effect of adenosine on the inhibition of leukotriene B4 (LTB4) synthesis in heparinized human whole blood, pretreated with lipopolysaccharide (LPS) and tumour necrosis factor alpha (TNF-alpha) and stimulated with the chemotactic peptide, N-formyl-Met-Leu-Phe (FMLP). 2. The FMLP-induced synthesis of LTB4 in whole blood pretreated with LPS and TNF-alpha was dose-dependently inhibited by adenosine analogues in the following order of potency; 5'(N-ethyl)carboxamidoadenosine (NECA) approximately equal to CGS 21680 > 2-Cl-adenosine > N6-cyclopentyladenosine (CPA), indicating the involvement of the adenosine A2 receptor subtype. The IC50 values for NECA, CGS 21680, 2-Cl-adenosine, and CPA were 6 nM, 9 nM, 180 nM, and 990 nM, respectively. 3. Dipyridamole, an agent that blocks the cellular uptake of adenosine by red cells and causes its accumulation in plasma, also inhibited the synthesis of LTB4 in LPS and TNF-alpha-treated whole blood stimulated by FMLP; moreover, this inhibition was reversed upon addition of adenosine deaminase. 4. A highly selective antagonist of the adenosine A2 receptor, 8-(3-chlorostyryl)caffeine (CSC), reversed the inhibition of LTB4 synthesis by 2-Cl-adenosine and dipyridamole in LPS and TNF-alpha-treated whole blood, stimulated by FMLP. 5. LTB4 synthesis in whole blood originates predominantly from neutrophils and to a lesser extent from monocytes. 2-Cl-adenosine also inhibited the synthesis of LTB4 induced by FMLP in these isolated LPS and TNF-alpha-treated cells; however, 2-Cl-adenosine was a more potent inhibitor of LTB4 synthesis in neutrophils than monocytes. 6. The present data demonstrate that adenosine, acting through A2 receptors, exerts a potent inhibitory effect on the synthesis of LTB4 and thus contribute to the understanding of its anti-inflammatory properties.