John R. Bethea
- Associate Professor, Department of Neurological Surgery
In my laboratory we are studying acute spinal cord injury to try to understand the cellular and molecular mechanisms that contribute to secondary neuronal cell death. To this end, my laboratory has two main research objectives. First, we are studying the neuro-inflammatory response that occurs following spinal cord injury (SCI) because we believe that inflammation is a central mediator of secondary neuronal injury. We are also looking for novel regulators of neuro-inflammation.
To determine what role(s) trauma-induced inflammation plays in mediating secondary neuronal injury and cell death following SCI, we use transgenic mouse models and other molecular biological approaches. We have recently demonstrated that traumatic SCI initiates a very robust inflammatory response, both within the spinal cord and systemically. Specifically, we have shown that traumatic SCI activates NF-kB within macrophages, microglia, endothelial cells and neurons. NF-kB is a transcription factor that plays a pivotal role in regulating inflammation, and possibly apoptotic cell death pathways. We have recently generated mice that do not express functionally active NF-kB in neurons and astrocytes and are currently studying spinal cord injury in mice.
The second major focus of my laboratory is to develop neuroprotective strategies for the treatment of acute SCI. To this end, we have begun investigating what effects the potent anti-inflammatory cytokine IL-10 has on trauma induced inflammation and the subsequent neuropathology of SCI. Our studies have demonstrated that systemic treatment with IL-10 after SCI significantly reduces trauma induces inflammation within the spinal cord and systemically. Furthermore, we have also demonstrated that IL-10 immunotherapy significantly reduces SCI induced neuropathology and the resulting secondary neuronal necrosis. The ultimate goal of the research in my laboratory is to develop effective therapeutic strategies for the treatment of SCI. We are also investigating pharmacological inhibition of pathways that are involved in secondary injury with the ultimate goal of developing new neuroprotective and regenerative strategies for SCI.
1: Yan D, Li F, Hall ML, Sage C, Hu WH, Giallourakis C, Upadhyay G, Ouyang XM, Du LL, Bethea JR, Chen ZY, Yajnik V, Liu XZ.
Abstract An Isoform of GTPase Regulator DOCK4 Localizes to the Stereocilia in the Inner Ear and Binds to Harmonin (USH1C).
J Mol Biol. 2006 Jan 23; [Epub ahead of print]
PMID: 16464467 [PubMed - as supplied by publisher]
2: Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S, Green EJ, Bethea JR.
Free Full Text Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury.
J Exp Med. 2005 Jul 4;202(1):145-56.
PMID: 15998793 [PubMed - indexed for MEDLINE]
3: Hu WH, Pendergast JS, Mo XM, Brambilla R, Bracchi-Ricard V, Li F, Walters WM, Blits B, He L, Schaal SM, Bethea JR.
Abstract NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation.
J Biol Chem. 2005 Aug 12;280(32):29233-41. Epub 2005 Jun 10.
PMID: 15951441 [PubMed - indexed for MEDLINE]
4: Hu WH, Mo XM, Walters WM, Brambilla R, Bethea JR.
Free Full Text TNAP, a novel repressor of NF-kappaB-inducing kinase, suppresses NF-kappaB activation.
J Biol Chem. 2004 Aug 20;279(34):35975-83. Epub 2004 Jun 18.
PMID: 15208311 [PubMed - indexed for MEDLINE]
5: Mingorance A, Fontana X, Sole M, Burgaya F, Urena JM, Teng FY, Tang BL, Hunt D, Anderson PN, Bethea JR, Schwab ME, Soriano E, del Rio JA.
Abstract Regulation of Nogo and Nogo receptor during the development of the entorhino-hippocampal pathway and after adult hippocampal lesions.
Mol Cell Neurosci. 2004 May;26(1):34-49.
PMID: 15121177 [PubMed - indexed for MEDLINE]
6: Hu WH, Walters WM, Xia XM, Karmally SA, Bethea JR.
Abstract Neuronal glutamate transporter EAAT4 is expressed in astrocytes.
Glia. 2003 Oct;44(1):13-25.
PMID: 12951653 [PubMed - indexed for MEDLINE]
7: Hu WH, Hausmann ON, Yan MS, Walters WM, Wong PK, Bethea JR.
Abstract Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP).
J Neurochem. 2002 Apr;81(1):36-45.
PMID: 12067236 [PubMed - indexed for MEDLINE]
8: Bethea JR, Dietrich WD.
Abstract Targeting the host inflammatory response in traumatic spinal cord injury.
Curr Opin Neurol. 2002 Jun;15(3):355-60. Review.
PMID: 12045737 [PubMed - indexed for MEDLINE]
9: Takami T, Oudega M, Bethea JR, Wood PM, Kleitman N, Bunge MB.
Abstract Methylprednisolone and interleukin-10 reduce gray matter damage in the contused Fischer rat thoracic spinal cord but do not improve functional outcome.
J Neurotrauma. 2002 May;19(5):653-66.
PMID: 12042099 [PubMed - indexed for MEDLINE]
10: Keane RW, Kraydieh S, Lotocki G, Bethea JR, Krajewski S, Reed JC, Dietrich WD.
Abstract Apoptotic and anti-apoptotic mechanisms following spinal cord injury.
J Neuropathol Exp Neurol. 2001 May;60(5):422-9.
PMID: 11379817 [PubMed - indexed for MEDLINE]
11: Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP.
Abstract Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat.
Exp Neurol. 2001 Mar;168(1):144-54.
PMID: 11170729 [PubMed - indexed for MEDLINE]
12: Bethea JR.
No abstract Spinal cord injury-induced inflammation: a dual-edged sword.
Prog Brain Res. 2000;128:33-42. Review. No abstract available.
PMID: 11105667 [PubMed - indexed for MEDLINE]
13: Laughlin TM, Bethea JR, Yezierski RP, Wilcox GL.
Abstract Cytokine involvement in dynorphin-induced allodynia.
Pain. 2000 Feb;84(2-3):159-67.
PMID: 10666520 [PubMed - indexed for MEDLINE]
14: Bethea JR, Nagashima H, Acosta MC, Briceno C, Gomez F, Marcillo AE, Loor K, Green J, Dietrich WD.
Abstract Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats.
J Neurotrauma. 1999 Oct;16(10):851-63.
PMID: 10547095 [PubMed - indexed for MEDLINE]
15: Brewer KL, Bethea JR, Yezierski RP.
Abstract Neuroprotective effects of interleukin-10 following excitotoxic spinal cord injury.
Exp Neurol. 1999 Oct;159(2):484-93.
PMID: 10506519 [PubMed - indexed for MEDLINE]
16: Dietrich WD, Busto R, Bethea JR.
Abstract Postischemic hypothermia and IL-10 treatment provide long-lasting neuroprotection of CA1 hippocampus following transient global ischemia in rats.
Exp Neurol. 1999 Aug;158(2):444-50.
PMID: 10415151 [PubMed - indexed for MEDLINE]
17: Bethea JR, Castro M, Keane RW, Lee TT, Dietrich WD, Yezierski RP.
Free Full Text Traumatic spinal cord injury induces nuclear factor-kappaB activation.
J Neurosci. 1998 May 1;18(9):3251-60.
PMID: 9547234 [PubMed - indexed for MEDLINE]
18: Bethea JR, Ohmori Y, Hamilton TA.
Abstract A tandem GC box motif is necessary for lipopolysaccharide-induced transcription of the type II TNF receptor gene.
J Immunol. 1997 Jun 15;158(12):5815-23.
PMID: 9190933 [PubMed - indexed for MEDLINE]
19: Bethea JR, Gillespie GY, Benveniste EN.
Abstract Interleukin-1 beta induction of TNF-alpha gene expression: involvement of protein kinase C.
J Cell Physiol. 1992 Aug;152(2):264-73.
PMID: 1639861 [PubMed - indexed for MEDLINE]
20: Bethea JR, Chung IY, Sparacio SM, Gillespie GY, Benveniste EN.
Abstract Interleukin-1 beta induction of tumor necrosis factor-alpha gene expression in human astroglioma cells.
J Neuroimmunol. 1992 Feb;36(2-3):179-91.
PMID: 1732280 [PubMed - indexed for MEDLINE]
21: Bethea JR, Gillespie GY, Chung IY, Benveniste EN.
Abstract Tumor necrosis factor production and receptor expression by a human malignant glioma cell line, D54-MG.
J Neuroimmunol. 1990 Nov;30(1):1-13.
PMID: 2172302 [PubMed - indexed for MEDLINE]
22: Benveniste EN, Sparacio SM, Bethea JR.
Abstract Tumor necrosis factor-alpha enhances interferon-gamma-mediated class II antigen expression on astrocytes.
J Neuroimmunol. 1989 Dec;25(2-3):209-19.
PMID: 2555395 [PubMed - indexed for MEDLINE]
23: Dietrich WD, Watson BD, Busto R, Ginsberg MD, Bethea JR.
Abstract Photochemically induced cerebral infarction. I. Early microvascular alterations.
Acta Neuropathol (Berl). 1987;72(4):315-25.
PMID: 3577687 [PubMed - indexed for MEDLINE]