ITIH4 (Inter-Alpha-Trypsin Inhibitor Heavy Chain 4) Is a New Acute-Phase Protein Isolated from Cattle during Experimental Infection

Abstract

We have isolated from calf serum a protein with an apparent M r of 120,000. The protein was detected by using antibodies against major acute-phase protein in pigs with acute inflammation. The amino acid sequence of an internal fragment revealed that this protein is the bovine counterpart of ITIH4, the heavy chain 4 of the inter-alpha-trypsin inhibitor family. The response of this protein in the sera was determined for animals during experimental bacterial and viral infections. In the bacterial model, animals were inoculated with a mixture of Actinomyces pyogenes, Fusobacterium necrophorum, and Peptostreptococcus indolicus to induce an acute-phase reaction. All animals developed moderate to severe clinical mastitis and exhibited remarkable increases in ITIH4 concentration in serum (from 3 to 12 times the initial values, peaking at 48 to 72 h after infection) that correlated with the severity of the disease. Animals with experimental infections with bovine respiratory syncytial virus (BRSV) also showed increases in ITIH4 concentration (from two-to fivefold), which peaked at around 7 to 8 days after inoculation. Generally, no response was seen after a second infection of the same animals with the virus. Because of the significant induction of the protein in the animals in the mastitis and BRSV infection models, we can conclude that ITIH4 is a new positive acute-phase protein in cattle.The acute-phase response occurs in animals as a consequence of infection, inflammation, or trauma. It is a nonspecific response mediated by inflammation-related cytokines (mainly by interleukin-6 [IL-6], IL-1, and tumor necrosis factor alpha) and is characterized by several systemic reactions, including fever, catabolism of muscle protein, alterations in sleep and appetite patterns, and changes in the concentrations of a group of serum proteins called acute-phase proteins (APP) (3,22,27,40).APP have been studied extensively in humans and in many animal species, mostly rats (38), though the panel of these proteins is probably not complete. The APP response differs among species. For domestic animals, the studies on APP are relatively recent (reviewed in reference 18). For cattle, several APP, including serum amyloid A, haptoglobin, alpha-1-acid glycoprotein, and alpha-1-proteinase inhibitor (alpha-1-antitrypsin), have been shown to increase in different inflammatory processes, in both in vivo (9,14,18,20,23,25,32) and in vitro models (2, 31). The course of infection in human patients is monitored by the determination of APP in blood samples (43), and a similar clinical use has been proposed for veterinary medicine (15,18,26) as well as for monitoring the health status of animals during farm production and at slaughter (42).In previous works from our laboratory, a new 120-kDa plasma glycoprotein, designated major acute-phase protein or pig MAP, was described as an APP occurring in pigs with turpentine-induced inflammation (16,29). This protein, which is also called porcine inter-alpha-trypsin inhibitor human-related protein (pig IHRP) (...

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

“…Thus far, numerous studies have shown involvement of ITIs in various pathological processes, including formation of urinary tract stones (Atmani and Khan, 1999;Janssen et al, 2001), female infertility (Zhuo et al, 2001), atherosclerosis and vascular disease (Onda et al, 1999;Fujita et al, 2004), and inflammation (Balduyck et al, 2000;Yingsung et al, 2003;Pineiro et al, 2004). Furthermore, several lines of evidence suggest a potential role of ITIs in tumour biology, particularly in the metastatic cascade and tumour progression (Kobayashi et al, 1995;Bourguignon et al, 1999;Paris et al, 2002;Zhang et al, 2004).…”

Identification of disease- and therapy-associated proteome changes in the sera of patients with myelodysplastic syndromes and del(5q)

“…Quantitative alteration of the fragments of inter-a trypsin inhibitor, heavy chain H4 was previously found to be associated with various cancer diseases, [22][23][24] indicating that the alteration of these species is not specific to MDS. Inter-a trypsin inhibitor, heavy chain H4 has been shown to be a positive acute phase protein in human and other animals, [25][26][27] thus the increase of these species might be associated with the inflammatory processes ongoing in MDS. 28 We also detected Proteomic analysis of serum proteome of myelodysplastic syndromes C Chen et al changes in transferrin, variants of transthyretin and haemoglobin a-and b-chains in diseased samples.…”

Pig Major Acute-Phase Protein and apolipoprotein A-I responses correlate with the clinical course of experimentally induced African Swine Fever and Aujeszky's disease

“…This protein was also referred to as PK-120 [26] or IHRP [36] being subsequently denominated ITIH4 (heavy chain 4 of the inter-alpha trypsin inhibitor family) [5]. Increases in the ITIH4 concentration under different physio-pathological situations have been reported in pigs [18,21,38], rats [10,17], bovines [30], humans [29,43] and mice [12]. In addition, we have previously reported that apolipoprotein A-I (apo A-I), the major protein component of high density lipoprotein (HDL), shows prominent decreases during experimental bacterial infection and acute inflammation [7,25].…”