Tissue Involution and the Acute Phase Response

Abstract

After their roles in reproduction are completed, the mass of the uterus and the mammary gland decrease rapidly by the process of involution that involves an ordered series of events including apoptosis, neutrophil entry, the release of degradative enzymes, and phagocytosis of cellular debris. The acute phase proteins are produced by the liver and other tissues in response to inflammation or a toxic challenge. Uterocalin (SIP24/24p3) is one of these proteins. During involution, the mammary gland and uterus express high levels of uterocalin that reach an average of 0.2-0.5% of the total extractable protein at its peak. Uterocalin and its orthologues have been demonstrated in vitro to (1). bind certain fatty acids and (2). specifically induce apoptosis in neutrophils and other leukocytes. The period of uterocalin expression during involution is consistent with the hypothesis that one of its physiological roles is to induce apoptosis of invading neutrophils and delay the entry of neutrophils into the tissue until the second phase of involution. Interestingly, it has been shown that uterocalin expression remains higher in primiparous gland than in virgin glands after the pregnant glands have completely involuted. This observation and the known protective effect of early pregnancy on later development of breast cancer suggest that the ability of uterocalin to induce apoptosis in neutrophils might also decrease oxidative and carcinogenic activity in the gland and result in a lower mutation rate and thus a lower probability of cancer in the primiparous gland.

Lipocalin 2-deficient mice exhibit increased sensitivity toEscherichia coliinfection but not to ischemia-reperfusion injury

“…To date, there has been only speculation about the role lipocalin 2 might play in this process. One hypothesis is that, because lipocalin 2 expression coincides with a high degree of apoptosis in an involuting tissue, lipocalin 2 may promote the cell death of invading neutrophils and thus delay neutrophil entry into a tissue until the second phase of involution (9). A proapoptotic function for lipocalin 2 has also been reported by Devireddy et al (10).…”

“…For instance, several lipocalins (including apolipoprotein D, quiescence-specific protein, purpurin, and ␣ 1 -microglobulin) have been implicated in the modulation of cell growth and metabolism, whereas others (␣ 1 -microglobulin, glycodelin, and lipocalin 2) appear to regulate the immune response (3)(4)(5)(6). Lipocalin 2 was originally described as an acute-phase protein in the liver (7) but is also up-regulated after LPS stimulation in macrophages (8) and in the lungs of LPS-treated mice (9). In addition, lipocalin 2 may be involved in tissue involution, a highly organized process of tissue restructuring.…”

“…In addition, lipocalin 2 may be involved in tissue involution, a highly organized process of tissue restructuring. During involution, lipocalin 2 levels can reach as high as 0.2-0.5% of the total extractable protein of the breast tissue (9). To date, there has been only speculation about the role lipocalin 2 might play in this process.…”

Identification of Common Transcriptional Regulatory Elements in Interleukin-17 Target Genes

“…24p3 was originally identified as an acute phase response gene induced in the liver, mainly by inflammatory stimuli such as TNF␣ and lipopolysaccharide (20,21). Diverse activities have been ascribed to 24p3, including roles in apoptosis, tissue involution, and ischemia-reperfusion injury (22)(23)(24). However, the most convincing function of 24p3 is its role in innate immune defense via iron sequestration.…”

Lipocalin 2-Dependent Inhibition of Mycobacterial Growth in Alveolar Epithelium

“…Lcn2 has been shown to mediate several biological processes, including mammary gland involution, induction of apoptosis, and delivery of iron (12,(17)(18)(19). In addition, structural studies have demonstrated that Lcn2 binds to enterobactin-type bacterial siderophores, which facilitate iron uptake by bacteria (16).…”