Under normal conditions, neutrophils roll along microvascular
walls via low affinity interaction of selectins with specific
endothelial carbohydrate ligands. During the inflammatory
response, chemotactic factors of different origin and
proinflammatory cytokines signal the recruitment of neutrophils to
sites of infection and/or injury. This leads to the activation of
neutrophil 
-integrins
and subsequent high-afinity binding to
intercellular adhesion molecules on the surface of activated
endothelial cells in postcapillary venules. Under the influence of
a chemotactic gradient, generated locally and by diffusion of
chemoattractants from the infection site, neutrophils penetrate the
endothelial layer and migrate through connective tissue to sites
of infection ( diapedesis),
where they finally congregate and
adhere to extracellular matrix components such as laminin and
fibronectin. A wide variety of adhesion molecules have been
characterized on the surface of phagocytic cells and will be shown
later.
Cytokines are basic regulators of all neutrophil
functions. Many of them including hematopoietic growth factors and
pyrogens have shown to be potent neutrophil priming agents.
Neutrophils also synthesize and secrete small amounts of some
cytokines including IL-1, IL-6, IL-8,
TNF-
, and GM-CSF; they may
act in an autocrine or paracrine manner. The pyrogenic
cytokines, IL-1, TNF-
,
and IL-6 all prime various pathways that
contribute to the activation of NADPH oxidase.
Pro-inflammatory cytokine IL-8, which is also known as
neutrophil-activating factor, is also a potent chemoattractant; it
synergizes with IFN-
, TNF-
,
GM-CSF, and G-CSF to amplify various
neutrophil cytotoxic functions. Cytokines also increase the
microbiostatic and killing capacities of neutrophils against
bacteria, protozoa and fungi. IFN-
and GM-CSF independently
amplify neutrophil antibody-dependent cytotoxicity.
Anti-inflammatory cytokines, IL-4 and IL-10 inhibit the
production of IL-8 and the
release of TNF-
and IL-1 which
reflects in the blockade of neutrophil activation.
Furthermore, some cytokines prolong neutrophil survival. The
acute inflammatory response may be terminated by the secretion of
macrophage inflammatory
protein-1
(MIP-1
) from neutrophils; this
protein may signal mononuclear cell recruitment and clear
neutrophils from the affected tissue site. All these cytokines are
produced by neutrophils themselves and/or by lymphocytes,
monocytes/macrophages or endothelial cells.
Along to cytokines other mediators, including bioactive lipids, neuroendocrine hormones, histamine, and adenosine, are also involved in the regulation of neutrophil activation.
Bioactive lipids originate mainly from arachidonic acid
which is an abundant constituent of neutrophil membranes.
Arachidonic acid is metabolized to prostaglandins, leukotrienes
and lipoxins. LTB
is a
strong neutrophil chemoattractant that may
play a role in the priming process. Vasoactive leukotrienes
LTC
, LTD
and LTE
increase
microvascular permeability and may
contribute to ischemia-reperfusion injury. In contrast to
leukotrienes, prostaglandins suppress most neutrophil
functions, possibly through their ability to elevate intracellular
cAMP. Lipoxins LXA
and LXB
are potent inhibitors of
neutrophil microbicidal activity.
In many inflammatory conditions, the level of platelet-activating factor (PAF) rise in the affected tissues, but injury can be attenuated by PAF antagonists. PAF directly primes superoxide generation and elastase release.
The major ''stress hormones'' are involved in the regulation of
inflammation at both the systemic and, perhaps, local levels. The
bidirectional interactions of cytokines and neurotransmitters with
nervous and immune cells, respectively, provide a means of
indirect chemical communication between the neuroendocrine and
immune systems. From the
neuroendocrine hormones mainly
growth hormone, prolactin, 
-endorphin,
glucocorticoids and
catecholamines are involved in the neutrophil regulation.
Growth hormone primes the oxidative burst of human neutrophils.
This is initiated by growth hormone to the prolactin (and not the
growth hormone) receptor on neutrophils in a zinc-dependent
process. The growth-promoting effects of growth hormone are
mediated through insulin-like growth factor 1, which is also
a strong neutrophil-priming agent. Prolactin, which shares
considerable functional and structural similarities with growth
hormone, is also a strong immunopotentiating agent. Prolactin
primes the oxidative burst of neutrophils and macrophages to the
same intensity as that induced by growth hormone.
Although glucocorticoids and opioids may enhance
some immune responses at very low concentrations, they are
generally considered to be immunosuppressive. These contrasting
responses may be controlled by the presence of multiple receptors
for the same mediator that are coupled to stimulatory and
inhibitory pathways. In fact, containment of the stress response
may be the principal role of glucocorticoids. Glucocorticoids
severely impair the phagocytic and cytotoxic activities of
neutrophils and macrophages, their capacity to produce ROI and to
induce iNOS, and secrete lysosomal enzymes in response to
activation. Oxidative burst of professional phagocytes is also
inhibited with epinephrine and 
-endorphin
which activity is
mediated via nonopioid receptors.
Histamine is a potent inhibitor of neutrophil
microbicidal activity. Adenosine provides an interesting
example of how a single mediators may play dual roles. Adenosine,
a vasodilator, is a potent anti-inflammatory agent released from
damaged host cells. Neutrophil chemotaxis is activated by
adenosine occupancy of 
receptors and inhibition of the
respiratory burst triggered through 
receptors. Adenosine
suppresses the respiratory burst only if it is added before the
triggering agent, but it has no effect on the initiation or
progress of degranulation.
The interactions between platelets and neutrophils are essential for both cell types. Activated platelets can bind to neutrophils and stimulate the oxidative burst while themselves synthesize vasoconstrictive leukotrienes. Like prostaglandins, many immunosuppressive mediators use cAMP as a second messenger. Increased intracellular cAMP in neutrophils is associated with decreases in a number of microbicidal functions. Phagocyte priming and activation may, in fact, be controlled by shifts in the intracellular ratio of cGMP to cAMP, since cGMP is stimulatory.