p21Cip1 Is Required for the Development of Monocytes and Their Response to Serum Transfer-induced Arthritis

Abstract

One of the central functions of cyclin-dependent kinase inhibitors, such as p21, p27, or p16, is to prevent entry into the cell cycle. However, the question remains as to whether they have other functions in the cell. We previously demonstrated that overexpression of p21 in fibroblasts isolated from patients with rheumatoid arthritis decreases the production of proinflammatory molecules. Overexpression of p21 has been also shown to reduce the development of experimental arthritis in mice and rats. To explore the role of endogenous p21 in the development of arthritis, we induced arthritis in p21 ؊/؊ mice using the K/BxN serum transfer model of arthritis. Mice deficient in p21 were more resistant to serum transfer-induced arthritis (K/BxN) than wild-type (wt) control mice. Fewer macrophages were detected in p21 ؊/؊ as compared to wt joints following transfer of K/BxN serum. Chemotaxis assays of bone marrow-derived macrophages from p21 ؊/؊ and wt mice revealed no difference in migration. However, there was a substantial decrease in inflammatory monocytes circulating in peripheral blood and in monocyte precursors in bone marrow of p21 ؊/؊ mice as compared to wt mice. Adoptive transfer of wt bone marrow-derived macrophages into p21 ؊/؊ mice restored the sensitivity to serum transfer-induced arthritis. These data suggest a novel role for p21 in regulating the development and/or differentiation of monocytic populations that are crucial for the induction of inflammatory arthritis.

p21Cip1 modulates arterial wound repair through the stromal cell–derived factor-1/CXCR4 axis in mice

“…We now additionally show that the hyperproliferative phenotype seen in p21 Cip1-/-mice is associated with an increased number of inflammatory macrophages in the early phase of vascular wound repair. While other researchers have investigated this phenomenon in different settings, our findings are broadly consistent with the fact that p21 Cip1 plays an important role in regulating cell proliferation and monocyte/macrophage differentiation (21,22). However, BM transplantation experiments demonstrated that the enhanced neointimal formation that was observed in p21 -/-mice could not be recapitulated by transplanting p21 -/-BM into p21 +/+ mice.…”

“…p21 Cip1 transcription is activated by p53, and p21 Cip1 is part of a negative feedback mechanism that controls p53 activity during apoptosis (20). p21 Cip1 has been shown to be an important mediator of inflammation, VSMC proliferation (21,22), and vascular proliferative disease (23)(24)(25)(26)(27). Of particular relevance, p21 knockout mice have been shown to exhibit enhanced neointimal formation following arterial injury (28).…”

Disruption of p21 Attenuates Lung Inflammation Induced by Cigarette Smoke, LPS, and fMLP in Mice

“…This is supported by the observations that p21-deficient (p212/2) mice are resistant to serum transfer-induced inflammatory arthritis (23), and peritoneal macrophages from p212/2 mice exhibit a higher phagocytotic capacity and lower expression of cytokines such as IL-1b, macrophage inflammatory protein (MIP)-1, and MIP-2 than do their wild-type (WT) counterparts (24). Moreover, genetic knockout of p21 attenuated angiotensin II-induced NF-kB activation by decreasing the production of reactive oxygen species (ROS) in vitro and in vivo (25).…”

Differential Macrophage Polarization in Male and Female BALB/c Mice Infected With Coxsackievirus B3 Defines Susceptibility to Viral Myocarditis

“…The severity of myocarditis was judged by percentage area of the myocardium with inflammation as described previously. 24,25 Five fields of view (ϫ100 magnification) of each slide were chosen randomly, and three different sections per mouse were examined. The entire areas of the fields and of regions affected by myocarditis were determined with the use of ImageJ software (NIH) and the percent area of the myocardium undergoing inflammation (affected/entire area in percent) was calculated and averaged.…”