p8 Improves Pancreatic Response to Acute Pancreatitis by Enhancing the Expression of the Anti-inflammatory Protein Pancreatitis-associated Protein I

Abstract

p8 is a transcription cofactor whose expression is strongly and rapidly activated in pancreatic acinar cells during the acute phase of pancreatitis. A p8-deficient mouse strain was generated as a tool to investigate its function. Upon induction of acute pancreatitis, myeloperoxidase activity in pancreas and serum concentrations of amylase and lipase were much higher and pancreatic lesions more severe in p8-deficient mice than in wild-type, indicating that p8 expression decreased pancreatic sensitivity to pancreatitis induction. The protective mechanism might involve the pancreatitisassociated protein (PAP I), whose strong induction during pancreatitis is p8-dependent, because administration of anti-PAP I antibodies to rats increased pancreatic inflammation during pancreatitis. In addition, 100 ng/ml PAP I in the culture medium of macrophages prevented their activation by tumor necrosis factor ␣, strongly suggesting that PAP I was an anti-inflammatory factor. Finally, PAP I was able to inhibit NFB activation by tumor necrosis factor ␣, in macrophages and in the AR42J pancreatic acinar cell line. In conclusion, p8 improves pancreatic resistance to inducers of acute pancreatitis by a mechanism implicating the expression of the anti-inflammatory protein PAP I.

Regulation of apoptosis by the p8/prothymosin α complex

“…Sequence identity of p8 and HMG-I͞Y is only Ϸ35%, but molecular mass, isoelectric points, hydrophilicity plots, and charge distributions along the polypeptides are very similar (5). An architectural role in transcription was proposed for p8 by analogy with HMG-I͞Y, and recent reports are consistent with this hypothesis (6)(7)(8).…”

“…Also, p8 activation stops cell growth upon nutriment deprivation in Drosophila melanogaster (14). Moreover, p8 is an important component of the defense program against lipopolysaccharide challenge (15), and it improves liver response to CCl 4 challenge (16) and pancreatic response to acute pancreatitis by enhancing the expression of the antiinflammatory protein PAP I (8). To account for these various functions, it is suggested that the small size of the protein, its lack of specific tridimensional structure, and its nuclear͞cytoplasmic localization (5) allow its interaction with several partners to target different signaling pathways.…”

Pancreatitis-Associated Protein-III Is a Novel Macrophage Chemoattractant Implicated in Nerve Regeneration

“…Furthermore, they identified a novel factor released from activated macrophages that induces neurite outgrowth of retinal ganglion cells more strongly than other tropic factors in vitro (Yin et al, 2003). Another probable function of PAP-III is to suppress macrophage release of cytotoxic cytokines around a nerve injury site because another family member, Reg-2/PAP-I, was reported to have anti-inflammatory potential on macrophages in acute pancreatitis (Vasseur et al, 2004). Although all the above-mentioned functions of PAP-III require further elucidation, it is likely that PAP-III has other beneficial functions in addition to macrophage chemoattraction for facilitating nerve regeneration.…”

Human Pancreatitis-associated Protein Forms Fibrillar Aggregates with a Native-like Conformation

“…Human PAP (hPAP) has been detected in several cancer tissues, such as liver and stomach (19,23), and has been identified as a biomarker for pancreatic ductal adenocarcinoma (24). Several biological functions of PAP have been proposed, including induction of bacterial aggregation (21), stimulation of cell proliferation (20), inhibition of apoptosis (25), and anti-inflammatory properties (26); however, its actual function is not known. PAP shows high sequence homology with lithostathine (LIT, also known as pancreatic stone protein or Reg1-encoded protein), another stress protein found in pancreatic juice (27).…”