Il8

Respiratory burst (4)

Collagen synthesis (-)

Increase in [Ca2^|l

Bioactiw lipids generation (t) / \ (loukolrtenes and platelet

P 1 adlvatlrtg IfKtor)

Lysosomal enzyme release (+)

Degranulallon (+)

Fibrobtasls

Figure 4 In vitro biological activities of IL-8.

causes a rapid (<30 min) mobilization of bone marrow stem cells into the peripheral blood in mice and primates. Intradermal injection of IL-8 induces a rapid and concentration-dependent neutrophil infil tration and neutrophil-dependent plasma leakage at the injected sites. In addition to neutrophils, local injection of IL-8 at a lower dose induces lymphocyte migration to the injected sites. In guinea pigs.

intravenous and intraperitoneal injections of IL-8 causes eosinophil accumulation in skin and lung, respectively.

Administration of neutralizing antibodies to IL-8 prevented neutrophil-dependent tissue injuries observed in several experimental models including lung perfusion injury, LPS-induced acute dermatitis, LPS- or IL-1-induced acute arthritis, immune complex-mediated acute glomerulonephritis, immune complex-mediated pneumonia, and aspiration pneumonia. These observations may implicate IL-8 as one of the major mediators of acute inflammation.

IL-8 transgenic mice (with expression of the trans-gene directed to either the liver or the gastrointestinal tract) exhibit increases in serum IL-8 levels and circulating neutrophil number, and decreases in L-selectin expression on the surface of neutrophils. They show an accumulation of neutrophils in the microcirculation of the lungs, liver and spleen without neutrophil extravasation, plasma exudate and tissue damage. No apparent change is observed on the bone marrow of the transgenic mice compared with the control littermates. However, neutrophil migration into the inflamed peritoneum is severely impaired in the transgenic mice.

Targeted disruption of the murine IL-8 receptor homolog gene (which has a high of homology with both the type A and type B human IL-8 receptors) results in lymphadenopathy due to an increase in B cells. Serum IL-6 level is also increased in IL-8 receptor-deficient mice. There is an increase in bone marrow cellularity composed of the normal myeloid cells in addition to splenomegaly resulting from an increase in myeloid cells in splenic white pulp. Neutrophil migration into the inflamed peritoneum is severely reduced although neutrophils retain their normal ability to kill bacteria. It should be noted that IL-8 receptor deficient mice, if kept in germ-free environments, do not develop increased myelo-poiesis, splenomegaly or lymphadenopathy.

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