Involvement of NF‐κB in the upregulation of cystathionine‐γ‐lyase, a hydrogen sulfide‐forming enzyme, and bladder pain accompanying cystitis in mice

Abstract

Hydrogen sulfide (H S) is generated from l-cysteine by multiple enzymes including cystathionine-γ-lyase (CSE), and promotes nociception by targeting multiple molecules such as Ca 3.2 T-type Ca channels. Bladder pain accompanying cyclophosphamide (CPA)-induced cystitis in mice has been shown to involve the functional upregulation of the CSE/H S/Ca 3.2 pathway. Therefore, we investigated whether NF-κB, as an upstream signal of the CSE/H S system, contributes to bladder pain in mice with CPA-induced cystitis. Bladder pain-like nociceptive behaviour was observed in CPA-treated mice, and referred hyperalgesia was evaluated by the von Frey test. Isolated bladder weights were assessed to estimate bladder swelling, and protein levels were measured by Western blotting. CPA, administered intraperitoneally, induced nociceptive behaviour, referred hyperalgesia and increased bladder weights in mice. β-Cyano-l-alanine, a reversible selective CSE inhibitor, prevented CPA-induced nociceptive behaviour, referred hyperalgesia, and, in part, increases in bladder weight. CPA markedly increased phosphorylated NF-κB p65 levels in the bladder, an effect that was prevented by pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor. PDTC and curcumin, which inhibits NF-κB signals, abolished CPA-induced nociceptive behaviour, referred hyperalgesia and, in part, increases in bladder weight. CPA caused the overexpression of CSE in the bladder, and this was prevented by PDTC or curcumin. The CPA-induced activation of NF-κB signals appeared to cause CSE overexpression in the bladder, contributing to bladder pain and in part swelling, possibly through H S/Ca 3.2 signaling. Therefore, NF-κB-inhibiting compounds including curcumin may be useful for the treatment of cystitis-related bladder pain.

Diallyl trisulfide, a H2S donor, inhibits cell growth of human papillary thyroid carcinoma KTC‐1 cells through a positive feedback loop between H2S and cystathionine‐gamma‐lyase

“…For instance, lipopolysaccharides upregulated CTH expression in primary human macrophages (Badiei, Gieseg, Davies, Izani Othman, & Bhatia, ), HEK‐293 and COS‐7 cells (Anderson & Rodwell, ) via NF‐κB pathway in vitro. Besides, activation of NF‐κB signals appeared to upregulate CTH overexpression in the bladder in a mice model (Ozaki, Tsubota, Sekiguchi, & Kawabata, ). Our results were consistent with the previous conclusion that NF‐κB activation was involved in the elevation of CTH induced by DATS in KTC‐1 cells (Figure ).…”

Involvement of Voltage-Gated Calcium Channels in Inflammation and Inflammatory Pain

“…3), considering that reversible and irreversible inhibitors of CSE, a H 2 S-generating enzyme, prevent the CPA-induced nociceptive behavior and referred hyperalgesia and that CPA treatment augments the expression and activity of CSE in the bladder. 10,77) The role of the H 2 S/ Ca v 3.2 pathway in bladder pain is supported by evidence that intravesical injection of the H 2 S donor NaHS causes prompt phosphorylation of ERK in the L6 spinal cord in anesthetized mice, an effect prevented by a T-type VGCC blocker. 10) The CPA-induced bladder pain and CSE upregulation involves substance P-induced NK 1 receptor activation 78) and nuclear factor-kappaB (NF-κB) signaling 77) (Fig.…”

“…Rodents treated with cyclophosphamide (CPA) mimic some of symptoms found in IC/BPS patients, including bladder pain and increased urinary frequency, 74,75) and have thus been used experimentally to clarify the mechanisms underlying the IC/BPS-related symptoms and to explore novel therapeutic targets for IC/BPS. 72) The CPA-induced cystitis/bladder pain is triggered by acrolein, a hepatic metabolite of CPA 76) (Fig. 3).…”

“…3), since T-type VGCC blockers, knockdown of Ca v 3.2 and inhibitors of CSE or NF-κB prevent the CPA-induced bladder swelling, in addition to bladder pain. 10,27,77) 4.3. Pancreatitis and Related Pain Acute pancreatitis often occurs secondarily to biliary diseases and alcohol abuse, and is characterized by inflammation in the pancreatic tissue (and in other organs in severe cases) and upper abdominal pain.…”

Role of macrophage–derived HMGB1 as an algogenic molecule ⁄ therapeutic target in visceral pain

“…を促進するが，CPA 18,30) is passively released from necrotic cells, and actively secreted by macrophages, etc. All-thiol HMGB1 activates the receptor for advanced glycation end-product (RAGE), while disulfide HMGB1, which has a disulfide bridge between C23 and C45, activates TLR4 by binding to MD2.…”