Prolonged Responses to Cytokines andor Hormones

Leukocytes produce a number of proinflammatory cytokines (TNF-a, IL-1a, IL-ip, IL-12, IFN-a, IFN-y, and IL-6) and anti-inflammatory cytokines (IL-1RA and transforming growth factor-^) in response to various agonists, including some of these cytokines. Studies of how IL-10 and IFN-y affect cytokine and chemokine production in LPS-stimulated neutrophils have revealed two distinct phases. In the early phase, there is a low level of chemokine release, directly induced by the LPS. This is followed by a second delayed phase, in which endogenous TNF-a and IL-1^ synergize with LPS in producing dramatically elevated levels of IL-8, macrophage inhibitory protein-1a (MIP-1a), MIP-1^, and growth-related gene product-a. This sequential production of chemokines by LPS-activated neutrophils, which is regulated by TNF-a and IL-1^, may serve to amplify the recruitment and activation of neutrophils and other leukocytes in vivo during an inflammatory response to LPS. IL-10 has also been shown to be a potent inhibitor of MIG induced by IFN-y and LPS. By regulating neutrophil-derived cytokine production, IL-10 may have an important regulatory

Fig. 2. Illustrates the effect on cell size of fMLP priming and PAR-2 activating peptide. Neutrophils were identified as in histogram A of Figure 1 and backgated to a histogram of forward scatter (FSC) and side scatter (SSC). Histogram A shows the light scattering properties of resting, unstimulated neutrophils. Upon addition of fMLP, the neutrophils swell and have increased forward scatter (histogram B). Addition of peptide that activates PAR-2 also stimulates an increase in size and forward scatter (histogram C). Histogram D shows the effect of priming the neutrophils with fMLP before addition of the activating peptide. There is an augmented increase in size and forward light scatter.

Forward scatter (size)

Fig. 2. Illustrates the effect on cell size of fMLP priming and PAR-2 activating peptide. Neutrophils were identified as in histogram A of Figure 1 and backgated to a histogram of forward scatter (FSC) and side scatter (SSC). Histogram A shows the light scattering properties of resting, unstimulated neutrophils. Upon addition of fMLP, the neutrophils swell and have increased forward scatter (histogram B). Addition of peptide that activates PAR-2 also stimulates an increase in size and forward scatter (histogram C). Histogram D shows the effect of priming the neutrophils with fMLP before addition of the activating peptide. There is an augmented increase in size and forward light scatter.

role in limiting the duration and extent of acute inflammatory responses (e.g., in lethal endotoxemia). Marie et al. (28) suggest that IL-10 produced during sepsis (29) reduces the production of IL-8 and may render neutrophils unresponsive to further stimulation by LPS. IL-4 and IL-13 have also been shown to have an inhibitory affect on neutrophil IL-8 production in the presence of LPS (30). The intracellular production of cytokines induced by culturing leukocytes with cytokines may be analyzed by flow cytometry and is discussed further in Chapter 8. The presence of cytokines both in vitro and in vivo also influences the expression of certain cell surface molecules such as such as CD69 (very early), CD71 (early), CD25 (late), and HLA-DR (very late) on lymphocytes (31); CD14, CD64, CD83, and chemokine receptors on neutrophils; CD143 and

CD163 on monocytes (32); and CD23, CD25, CD69, CD105, and CD153 on macrophages (33). Recently, cytokine-activated neutrophils with enhanced expression of cell surface molecules have been shown to become as competent as dendritic cells and macrophages in their ability to undertake antigen presentation (33,34).

Hormones such as growth hormone have been shown to reduce phagocytic and metabolic function in neutrophils. This is the result of reduced TNF production (35). Glucocorticoids have also been shown to block PAF-induced downregulation of CD62L and upregulation of CD11/CD18 on neutrophils. This suggests that ligation of glucocorticoid receptors has an anti-inflammatory effect on cells by the inhibition of leukocyte accumulation at sites of tissue injury (36).

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