Anti-TAC4 (aa 92-113) polyclonal antibody

Human hemokinin-1 (h HK-1) and its truncated form h HK-1 (4-11) are mammalian tachykinin peptides encoded by the TAC4 gene identified in human, and the biological functions of these peptides have not been well investigated. The tachykinins have shown immuno-regulatory activities in humans. In the present study, we investigated the effects of h HK-1 and h HK-1(4-11) on the proliferation and differentiation of a human promyelocyte leukemia cell line, HL-60. It is noteworthy that h HK-1 (1-300 mu M) displayed inhibitory effects on the proliferation of HL-60 cells in a dose- and time-dependent manner. The effect of suppressing proliferation induced by these peptides was accompanied by an accumulation of cell cycle in the S phase. Moreover, this peptide induced differentiation of HL-60 cells by significantly increasing the NBT-reduction activity. The effects induced by h HK-1 (4-11) on HL-60 cells were similar to that of h HK-1, indicating that it is the active fragment of h HK-1. However these effects induced by h HK-1 or h HK-1 (4-11) were not antagonized by the NK1 receptor antagonist SR140333 or the NK2 receptor antagonist SR48968. All the results indicated that h HK-1 and h HK-1(4-11) were able to significantly inhibit proliferation and induce differentiation and S phase arrest of a human promyelocyte leukemia cell line HL-60, which may not be mediated through the activation of classical tachykinin NK1 receptors and tachykinin NK2 receptors. Our observations also implied that h HK-1 and h HK-1 (4-11) could act as immunomodulatory factors in cancer chemotherapy. (C) 2009 Elsevier Inc. All rights reserved.

The tachykinin NK1 receptor was suggested to be involved in psychiatric disorders, but its antagonists have failed to be effective as antidepressants in clinical trials. Hemokinin-1 (HK-1), the newest tachykinin, is present in several brain regions and activates the NK1 receptor similarly to substance P (SP), but acts also through other mechanisms. Therefore, we investigated the roles of the Tac4 gene-derived HK-1 in comparison with SP and neurokinin A (NKA) encoded by the Tac1 gene, as well as the NK1 receptor in anxiety and depression-like behaviors in mice. Mice lacking SP/NKA, HK-1 or the NK1 receptor (Tac1(-/-), Tac4(-/-), Tacr1(-/-), respectively) compared to C57Bl/6 wildtypes (WT), and treatment with the NK1 antagonist CP99994 were used in the experiments. Anxiety was evaluated in the light-dark box (LDB) and the elevated plus maze (EPM), locomotor activity in the open field (OFT) tests. Hedonic behavior was assessed in the sucrose preference test (SPT), depression-like behavior in the tail suspension (TST) and forced swim (FST) tests. FST-induced neuronal responsiveness was evaluated with Fos immunohistochemistry in several stress-related brain regions. In the LDB, Tac4(-/-) mice spent significantly less, while Tacr1(-/-) and CP99994-treated mice spent significantly more time in the lit compartment. In the EPM only Tac4(-/-) showed reduced time in the open arms, but no difference was observed in any other groups. In the OFT Tac4(-/-) mice showed significantly reduced, while Tac1(-/-) and Tacr1(-/-) animals increased motility than the WTs, but CP99994 had no effect. NK1(-/-) consumed markedly more, while Tac4(-/-) less sucrose solution compared to WTs. In the TST and FST, Tac4(-/-) mice showed significantly increased immobility. However, depression-like behavior was decreased both in cases of genetic deletion and pharmacological blockade of the NK1 receptor. FST-induced neuronal activation in different nuclei involved in behavioral and neuroendocrine stress responses was significantly reduced in the brain of Tac4(-/-) mice. Our results provide the first evidence for an anxiolytic and anti-depressant-like actions of HR-1 through a presently unknown target-mediated mechanism. Identification of its receptor and/or signaling pathways might open new perspectives for anxiolytic and anti-depressant therapies. 2016 Elsevier Inc. All rights reserved.