Association of pro/anti-inflammatory cytokine gene variants in renal transplant patients with allograft outcome and cyclosporine immunosuppressant levels

Manchanda, Parmeet Kaur; Kumar, Anant; Sharma, Raj Kumar; Goel, Himanshu; Mittal, Rama Devi

doi:10.2147/btt.s2459

Cited by 3 publications

(1 citation statement)

References 37 publications

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“…The induction of inflammatory cytokines and chemokines, known to stimulate many STAT protein cascades, is a hallmark of kidney graft failure [ 50 , 51 ]. While inflammatory cytokines such as TNF-α and IFNs are known to activate/induce STAT1 and STAT3 [ 39 , 52 , 53 , 54 , 55 ] we do not know if these cytokines transmit inflammatory signals through STAT1 and STAT3 during CS + Tx.…”

Section: Introductionmentioning

confidence: 99%

Cold Storage Followed by Transplantation Induces Interferon-Gamma and STAT-1 in Kidney Grafts

McGraw

Miller

et al. 2023

IJMS

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Cold storage (CS)-mediated inflammation, a reality of donor kidney processing and transplantation, can contribute to organ graft failure. However, the mechanisms by which this inflammation is perpetuated during and after CS remain unclear. Here, we examined the immunoregulatory roles of signal transducer and activator of transcription (STAT) family proteins, most notably STAT1 and STAT3, with our in vivo model of renal CS and transplant. Donor rat kidneys were exposed to 4 h or 18 h of CS, which was then followed by transplantation (CS + transplant). STAT total protein level and activity (phosphorylation) were evaluated via Western blot analysis and mRNA expression was tabulated using quantitative RT-PCR after organ harvest on day 1 or day 9 post-surgery. In vivo assays were further corroborated via similar analyses featuring in vitro models, specifically proximal tubular cells (human and rat) as well as macrophage cells (Raw 264.7). Strikingly, gene expression of IFN-γ (a pro-inflammatory cytokine inducer of STAT) and STAT1 were markedly increased after CS + transplant. STAT3 dephosphorylation was additionally observed after CS, a result suggestive of dysregulation of anti-inflammatory signaling as phosphorylated STAT3 acts as a transcription factor in the nucleus to increase the expression of anti-inflammatory signaling molecules. In vitro, IFN-γ gene expression as well as amplification of downstream STAT1 and inducible nitric oxide synthase (iNOS; a hallmark of ischemia reperfusion injury) was remarkably increased after CS + rewarming. Collectively, these results demonstrate that aberrant induction of STAT1 is sustained in vivo post-CS exposure and post-transplant. Thus, Jak/STAT signaling may be a viable therapeutic target during CS to mitigate poor graft outcomes when transplanting kidneys from deceased donors.

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