CC chemokines regulate the function of neutrophils that enhance immune response

• Main Authors: Yi-Hsien Huang, 黃議賢
• Other Authors: Ching Li
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/34030675113545108844

碩士 === 中山醫學大學 === 免疫學研究所 === 92 === Abstract Chemokines are a group of small peptides composed of 70-130 amino acids with molecular weight of 8-14 kDa, and distinguished into four groups: C, CC, CXC, and CX3C, according to their final two cystein of the amine bases. CC Chemokines have been described as primary components of human immunodeficiency virus type 1 (HIV-1) suppressive soluble factors in vitro. Previous study stated that 9 Chinese subjects in Taiwan were sexually exposed to HIV carriers and remained uninfected, these subjects found to have large quantities of CC chemokines (MIP-1α, MIP-1β, and RANTES) in the serum. In addition, an interesting phenomenon was discovered in present study as these subjects were found to have lots of low density neutrophils in their body. Therefore, we propose that possible interplay of CC chemokines and neutrophils that might potentially contribute to the protection of the immune system. As recombinant CC chemokines (MIP-1α, MIP-1β, and RANTES) were incubated with neutrphils, it is found that changing of the cellular volume of neutrophils and the granules within the cells leads to changes in neutrophil density without prior priming. Such a change can abolish by CCR1, CCR3, and CC5 specific antibody. By using confocal spectral microscopy and flow cytometry, we provided substantial evidences that all recombinant MIP-1α, MIP-1β, and RANTES could rapidly induce human neutrophils to undergo degranulation in vitro that results in release of a large quantity of α-defensins. On the other hand, chemokines play a major role in the recruitment of leukocytes to sites of infection. When analyzed in vitro with microchamber chemotaxis assays, MIP-1α, MIP-1β, and RANTES were shown to be potent chemo-attractants of neutrophils dose-dependently. There are papers showing that the chemo-attractant receptors can couple to Gi proteins, a class of G protein that is sensitive to Pertussis toxin (PTx). By using the phosphatidylinositol-3-kinase (PI3K) and c-Jun N-terminal kinase (JNK) specific inhibitors, LY294002 and SP6000125, We have demonstrated that PI3K and JNK activities were required for CC chemokines-mediated induction of neutrophil migration. Since neutrophils play a crucial role in the first-line defense against invading microorganisms by a process known as phagocytosis, fluorescent conjugate beads were used to determine CC chemokines-treated neutrophils phagocytosis activity in this study, and found that CC chemokines can increase the engulfing ability of neutrophils. Our results demonstrated that the CC chemokines not only stimulate neutrophils degranulation and to release large mount of α-defensins, but also enhance the neutrophils ability of carrying out phagocyosis. Since neutrophils are the most abundant white blood cells, and can be simultaneously activated to release α-defensins which possess antiviral activity, our results support that neutrophils are involved in innate immunity that participate in the inactivation of nonspecific invading viruses, including HIV.