Initial efforts have been made to identify and characterize the annexins, particularly annexin I and II, as possible second messengers in response to antiinflammatory steroids. The observations to date have shown that these recombinant annexins are able to mimic a part, if not all, of the anti-inflammatory action of glucocorticoids, while antibodies against annexins diminish such actions (Table 2). Even some of their fragments containing the N-terminus exhibit similar but weak anti-inflammatory actions. The inflammatory reactions inhibited by annexins and their fragments include not only the release of arachi-donate and its metabolites and the formation of PAF but also neutrophil chemotaxis and release of lyso-zymes. The cytotoxic reaction by cytotoxic T cells and NK cells is also inhibited by both annexins and glucocorticoids. Although the annexin I and II genes contain GRE sequences in their 5'-flanking regions, thus implicating transcriptional regulation by glucocorticoids, induction of the synthesis of annexins by the steroids remains to be determined. Such indue-
Table 2 Biological action of annexins
1. Inflammatory responses a) Inhibition of in vivo inflammation
Carrageenan-induced paw edema and pleurisy b) Inhibition of in vitro inflammatory response
Inhibition of neutrophil chemotaxis Slight inhibition of O5 production Inhibition of lysozyme release Inhibition of phagocytosis Inhibition of arachidonic acid liberation Inhibition of PAF formation
2. Immune system a) In vivo
Tumor-induced immunosuppression Modulation of in vivo pyrogenic action by cytokines
Suppression of IgE synthesis b) In vitro
Inhibition of cytotoxic reaction of cytotoxic T cells and NK cells
Inhibition of in vitro cytotoxic T cell generation
Inhibition of IL-1 production
Inhibition of IL-1 action
Inhibition of IL-2 production
Inhibition of T cell proliferation
Induction of maturation of suppressor T cells
Induction of memory cells
Inhibition of IgE synthesis
Change from necrosis to apoptosis of H202-
Differentiation of leukemia cell lines Differentiation of macrophage cell lines Differentiation of neuronal cell lines Differentiation of glial cell lines Differentiation of fibroblast cell lines Differentiation of epidermal cell lines Differentiation of epithelial cell lines
4. Secretion a) Inhibition of ACTH, TSH, prolactin and other peptide hormones from pituitary cells b) Inhibition of catecholamines from chromaffin cells
5. Other biological actions a) Inhibition of in vitro coagulation b) Inhibition of in vivo brain edema c) In vitro mucous production of tracheas d) In vitro induction of /3-adrenoceptors and/or inhibition of ^-adrenoceptor downregulation e) Inhibition of in vivo LPS induction of nitric oxide (NO) synthetase f) Enhancement of DNA replication in the oocyte cell free system and in mitochondria g) Osteoclast formation and bone reabsorption tion has been often demonstrated in intact animals and organs, while cultured cells mostly fail to respond to glucocorticoids at either mRNA or protein levels. Since a whole family of annexin proteins which maintain a highly conserved structure in the C-terminal core with each other, occupy approximately 2% of the total cellular proteins, and since their synthesis is dependent on the cell cycle, changes in their mRNA and/or protein levels might be often underestimated. Alternatively, an unknown mechanism beside the genomic effect of glucocorticoids might be involved in induction of the synthesis of annexin I and II.
Most annexins are localized intracellularly, particularly in the cytosol. However, various stimuli including increased intracellular Ca2+ are known to translocate annexins to plasma membranes and other subcellular vesicles including chromaffin granules. Glycosylation and acylation of annexins is thought to be important for such insertion and/or attachment to membranes. Some annexins are known to be extracellularly released. Autoantibodies against annexins in patients with rheumatoid arthritis and systemic lupus erythematosus (SLE) neutralize these annexins, thereby augmenting inflammatory responses in these diseases. Similar observations have been extended to inflammatory diseases such as asthma, psoriasis, and ulcerative colitis. Among these diseases, SLE may involve dysfunction of suppressor T cells in the immune system. During immunoglobulin E (IgE) synthesis in vitro annexin I enhances suppressor function by inhibiting the glycosylation of IgE-binding factor.
Similarly, annexins regulate the proliferation-differentiation of suppressor T cells, including cytotoxic T cells. This leads to the suggestion that the immunosuppression of animals bearing tumors can be attributed to monocytes/macrophages in which the synthesis of annexin I is stimulated. Because of the chemical nature of annexin I and II as substrates for tyrosine kinases, including EGF receptor kinase and Src kinases, annexins are associated with the proliferation-differentiation process of many cells other than suppressor T cells (Table 2). Effects of annexins, especially annexin I and II, are similar, if not identical, to those of glucocorticoids. However, the mechanism of action of exogenous annexins cannot be explained by their binding to plasma membrane acidic phospholipids, which are mainly located on the intracellular side of the membranes. In fact, the binding of annexin V is currently used to detect apoptotic cells which have an inverted membrane phospholipid distribution. This suggests that the existence of specific receptors for annexins mediate their actions. Alternatively, annexins may be inserted into membranes to interact with specific enzymes and/or proteins.
Annexin VII has been identified as synexin, a protein which modulates presynaptic functions including the release of neurotransmitters. Similarly, other annexins are reported to participate in exocytosis and endocytosis in a variety of cell functions such as catecholamine release from adrenal chromaffin cells and ACTH secretion from pituitary cells. Such activity is attributed to the binding of annexins to subcellular vesicle membranes and Ca2_f channel and/or sensor action, although the possibility of an interaction between annexins and actin-like cyto-skeletal elements, thus changing their bundling, cannot be neglected.
The presence of annexins in nuclei and mitochondria has also been reported. Although annexin II can regulate the replication of DNA in cell-free systems, the detailed mechanism(s) remains to be solved. Since annexin 1 and II and annexin I-IV have phosphorylation sites for tyrosine protein kinases and protein kinase C (enzymes that regulate the proliferation-differentiation and/or cell cycle of cells) respectively, many reports describe their involvement in the proliferation-differentiation processes of various cells. Such phosphorylation of annexins alters their affinities for Ca2+ and phospholipids, and their interactions with other enzymes and/or proteins. A recent report describing the involvement of annexin I in the apoptosis of H202-trcated thymocytes may also substantiate this contention, because apoptosis, a type of cell death distinct from necrosis, is explained by an abortive cell activation mechanism.
Although the structure and chemical and physical nature of annexins have been extensively studied, the mechanism of most of their biological and physiological actions remain unclear. Considering the unique distribution of certain annexins in specific cell types, it is likely that additional physiological and/or biological roles and mechanisms of actions of the annexin family of proteins will be explored in the near future.
See also: Acute inflammatory reaction; Arachidonic acid and the leukotrienes; Autoimmune diseases; Glucocorticoids; Hypersensitivity reactions; Platelet-activating factor (PAF); Proliferation, lymphocyte; Prostaglandins.
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