Inflammation 5(
S)-HETE and other family members were first detected as products of arachidonic acid made by stimulated human polymorphonuclear neutrophils (
PMN), a leukocyte blood cell type involved in host immune defense against infection but also implicated in aberrant pro-inflammatory immune responses such as arthritis; soon thereafter they found to be active also in stimulating these cells to migrate (i.e. chemotaxis), degranulate (i.e. release the anti-bacterial and tissue-injuring contents of their granules), produce bacteriocidal and tissue-injuring
reactive oxygen species, and mount other pro-defensive as well as pro-inflammatory responses of the
innate immune system. For example, the
gram-negative bacterium,
Salmonella tryphimurium, and the outer surface of gram-negative bacteria
lipopolysaccharide, promote the production of 5(
S)-HETE and 5-oxo-ETE by human neutrophils. The family members stimulate another blood cell of the
innate immunity system, the human
monocyte, acting synergistically with the pro-inflammatory
CC chemokines,
monocyte chemotactic protein-1 and monocyte chemotactic protein-3, to stimulate monocyte function. 5-Oxo-ETE also stimulates two other cell types that share responsibility with the PMN for regulating inflammation, the human
lymphocyte and
dendritic cell. And,
in vivo studies, the injection of 5-oxo-ETE into the skin of human volunteers causes the local accumulation of PMN and monocyte-derived
macrophages. These results given above suggest that members of the 5-oxo-ETE family and the OXER1 receptor or its orthologs may contribute to protection against microbes, the repair of damaged tissues, and pathological inflammatory responses in humans and other animal species. Additionally, cultured human airway epithelial cell lines, normal bronchial epithelium, and bronchial smooth muscle cells convert 5(
S)-HETE to 5-oxo-ETE in a reaction that is greatly increase by oxidative stress, which is a common component in allergic inflammatory reactions. Among the 5-HETE family of metabolites, 5-oxo-ETE is implicated as the most likely member to contribute to allergic reactions. It has exceptionally high potency in stimulating the
chemotaxis, release of granule-bound tissue-injuring enzymes, and production of tissue-injuring reactive oxygen species of a cell type involved in allergic reactions, the human
eosinophil granulocyte. PAF is itself a proposed mediator of human allergic reactions which commonly forms concurrently with 5-HETE family metabolites in human leukocytes and acts synergistically with these metabolites, particularly 5-oxo-ETE, to stimulate eosinophils. 5-Oxo-ETE also cooperates positively with at least four other potential contributors to allergic reactions,
RANTES,
eotaxin,
granulocyte macrophage colony-stimulating factor, and
granulocyte colony-stimulating factor in stimulating human eosinophils and is a powerful stimulator of chemotaxis in another cell type contributing to allergic reactions, the human
basophil granulocyte. The role of 5-HETE family agonists in the
bronchoconstriction of airways (a hallmark of allergen-induced asthma) in humans is currently unclear. 5-HETE stimulates the contraction of isolated human bronchial muscle, enhances the ability of histamine to contract this muscle, and contracts guinea pig lung strips. 5-Oxo-ETE also stimulates contractile responses in fresh bronchi, cultured bronchi, and cultured lung smooth muscle taken from guinea pigs but in direct contrast to these studies is reported to relax bronchi isolated from humans. The latter bronchi contractile responses were blocked by cyclooxygenase-2 inhibition or a thromboxane A2 receptor antagonist and therefore appear mediated by 5-oxo-ETE-induced production of this thromboxane. In all events, the relaxing action of 5-oxo-ETE on human bronchi does not appear to involve OXER1.
Steroid production 5(
S)-HETE and 5(
S)-HpETE stimulate the production of
progesterone by cultured rat ovarian glomerulosa cells and enhance the secretion of progesterone and
testosterone by cultured rat testicular
Leydig cells. Both metabolites are made by
cyclic adenosine monophosphate-stimulated
MA-10 mouse Leydig cells; stimulate these cells to transcribe
steroidogenic acute regulatory protein, and in consequence produce the
steroids. The results suggest that trophic hormones (e.g.,
leutenizing hormone,
adrenocorticotropic hormone) stimulate these steroid producing cells to make 5(
S)-HETE and 5(
S)-HpEPE which in turn increase the synthesis of steroidogenic acute regulatory protein; the latter protein promotes the rate-limiting step in steroidogenesis, transfer of cholesterol from the outer to the inner membrane of mitochondria and thereby acts in conjunction with trophic hormone-induce activation of protein kinase A to make progesterone and testosterone. This pathway may also operate in humans: Human
H295R adrenocortical cells do express OXER1 and respond to 5-oxo-ETE by an increasing the transcription of steroidogenic acute regulatory protein messenger RNA as well as the production of aldosterone and progesterone by an apparent OXER1-dependent pathway. Rat and mouse cells lack OXER1. It has been suggested that the cited
mouse MA-10 cell responses to 5-oxo-ETE are mediated by an ortholog to OXER1, mouse
niacin receptor 1, Niacr1, which is a G protein-coupled receptor mediating the activity of
niacin, or by one or more of the mouse hydroxycarboxylic acid (HCA) family of the G protein-coupled receptors, HCA1 (
GPR81), HCA2 (
GPR109A), and HCA3 (
GPR109B), which are G protein-coupled receptors for fatty acids. It also inhibits morphogenetic protein-2 (BMP-2)-induced bone-like nodule formation in mouse calvarial organ cultures. These results allow that 5(
S)-HETE and perhaps more potently, 5-oxo-ETE contribute to the regulation of
bone remodeling.
Parturition 5(
S)-HETE is: elevated in the human uterus during
labor; at 3–150
nM, increases both the rates of spontaneous contractions and overall contractility of myometrial strips obtained at term but prior to labor from human lower uterine segments; and in an
in vitro system crosses either
amnion or intact amnion-chorion-decidua and thereby may along with
prostaglandin E2 move from the amnion to uterus during labor in humans. These studies allow that 5(
S)-HETE, perhaps in cooperation with established role of prostaglandin E2, may play a role in the onset of human labor.
Other actions 5(
S)-HETE is reported to modulate
tubuloglomerular feedback. 5(
S)-HpETE is also reported to inhibit the
-ATPase activity of
synaptosome membrane preparations prepared from rat
cerebral cortex and may thereby inhibit synapse-dependent communications between neurons. 5(
S)-HETE acylated into phosphatidylethanolamine is reported to increase the stimulated production of
superoxide anion and interleukin-8 release by isolated human neutrophils and to inhibit the formation of
neutrophil extracellular traps (i.e. NETS); NETS trap blood-circulating bacteria to assist in their neutralization. == See also ==