Effectors chemotaxis

CC, and one CX3C and XC chemokine receptors have been cloned so far [2]. Receptor binding initiates a cascade of intracellular events mediated by the receptor-associated heterotrimeric G-proteins. These G-protein subunits trigger various effector enzymes that lead to the activation not only of chemotaxis but also to a wide range of fimctions in different leukocytes such as an increase in the respiratory burst, degranulation, phagocytosis, and lipid mediator synthesis. 

Mechanisms of Complement Activation. Complement is a major mediator of the inflammatory response. Complement recruits and enlists the participation of humoral and cellular effector systems, induces histamine release from mast cells and directs migration of leukocytes (chemotaxis), in addition to producing phagocytosis and the release of lysosomal constituents from phagocytes. 

Potential etiologic agents in cotton dust that release histamine are shown in Table VII. Some of these are effector molecules having potent biological effects in minute concentrations, i.e. peptides, which may act directly to affect chemotaxis and leukocyte recruitment, and also to release histamine and stimulate respiratory smooth muscle contraction. These bifunctional effector molecules are of major importance in considering pathogenic mechanisms in byssinosis. 

The most relevant bioassays measure specific activities on immune function, either as effector or regulatory, for example, assay of cytokine IL-12 by the augmentation of the cytolytic function of natural killer cells (B9), IL-10 by the inhibition of the production of TNF-o from stimulated monocytes (B13), and IL-8 and eotaxin by the chemotaxis of neutrophils and eosinophils, respectively (C2). 

Fig. 2. Minimal components of the G protein-coupling cycle in a schematic chemotaxis pathway. (A) Chemotaxis G protein-coupled receptors reside in the plasma membrane associated with specific heterotrimeric G proteins. (B) Upon binding of a chemoattractant such as fMLF, the receptor catalyzes the exchange of GTP for GDP in the a subunit of the G protein, thereby dissociating the GTP-bound a subunit from the (3 subunit complex. Chemotaxis GPCRs typically utilize the a isoform of the a subunit. (C) Subsequently the dissociated GTP-bound a subunit and the j3 subunit complex each dock to effectors elsewhere in the cell. (D) The a subunit possesses intrinsic GTPase activity that hydrolyzes the bound GTP to GDP, thereby regenerating the GDP-bound Oj subunit that reassociates with the / 7 subunit complex and with the receptor. Bordetella pertussis toxin covalently and specifically modifies the isoform of the a subunit and prevents its association with receptor (see text for additional discussion and references).

N-formylmethionyl peptide receptors (FPR) are chemoattractant receptors on phagocytic cells like human neutrophils. Stimulation of FPR with N-formylmethionyl peptides induces a variety of responses of these cells including chemotaxis, superoxide production, release of hydrolytic enzymes and reorganization of cytoskeletal structures [36,37]. Most of these responses appear to be mediated through activation of phospholipase C, however, participation of other effector enz)nnes such as adenylyl cyclase, phospholipase D and phospholipase A2 have also been demonstrated [38]. 

There has been a great deal of interest in chemokine receptor signalling in cancer in terms of the specific pathways and effector molecules that regulate cell survival, proliferation, chemotaxis, migration and adhesion. It is clear that a large number of downstream effector molecules that are regulated by chemo-kines may account for the multiple effects of these receptors in the pathobiology... 

Pheromone production and perception form a very common means of chemical communication between different individuals of a society, and it is especially developed for well defined molecules among insects. In this case the molecular mechanism of transduction is not very different from that of olfactory perception. On the other hand, chemical signals also exist between microorganism, and chemotaxis is a widespread phenomenon leading to cell motion. Especially bacterial chemotaxis is an important mechanism in the nutrition of mobile bacteria and their protection from toxic substances. Hence the effector substances are not as specialized as pheromones, but rather are molecules of more general availability [19]. 

Chemokines induce directed chemotaxis in nearby responsive cells. They are released from various cells in response to bacteria and viruses infection and in response to agents that cause physical damage such as silica or urate crystals. The main functions of chemokines are chemoattractants for leukocytes. They help to recruit monocytes, neutrophils, and other effector cells from the blood to the sites of infection or damage. They serve to guide cells involved in innate immunity and in the adaptive immune system. Some chemokines have other roles in the development of lymphocytes, migration, and the growth of new blood vessels. 

The biological actions of capsaicin are primarily attributable to release of the neuropeptide substance P, calcitonin gene-related peptide (CGRP), and neurokinin A from sensory neurons. These transmitters from primary sensory neurons communicate witir other cell types. They produce alterations in the airway mucosa and neurogenic inflammation of the respiratory epithelium, airway blood vessels, glands, and smooth muscle. Alterations in multiple effector organs lead to bronchoconstriction, increased vascular permeability, edema of the tracheobronchial mucosa, elevated mucosal secretion, and neutrophil chemotaxis (Tominack and Spyker, 1987). Capsaicin-induced effects of bronchoconstriction, vasodilation, and plasma protein extravasation are mediated by substance P. In addition, substance P can cause bronchoconstriction through stimulation of c-fibers in pulmonary and bronchial circulation. 

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