Ciliary neurotrophic factor potentiates the beta-cell inhibitory effect of IL-1beta in rat pancreatic islets associated with increased nitric oxide synthesis and increased expression of inducible nitric oxide synthase.

Abstract

Proinflammatory cytokines are implicated as effector molecules in the pathogenesis of IDDM. Interleukin-6 (IL-6) alone or in combination with IL-1beta inhibits glucose-stimulated insulin release from isolated rat pancreatic islets by unknown mechanisms. Here we investigated 1) if the effects of IL-6 are mimicked by ciliary neurotrophic factor (CNTF), another member of the IL-6 family of cytokines signaling via gp130, 2) the possible cellular mechanisms for these effects, and 3) if islet endocrine cells are a source of CNTF. CNTF (20 ng/ml) potentiated IL-1beta-mediated (5-150 pg/ml) nitric oxide (NO) synthesis from neonatal Wistar rat islets by 31-116%, inhibition of accumulated insulin release by 34-49%, and inhibition insulin response to a 2-h glucose challenge by 31-36%. CNTF potentiated IL-1beta-mediated NO synthesis from RIN-5AH cells by 83%, and IL-1beta induced islet inducible NO-synthase (iNOS) mRNA expression fourfold. IL-6 (10 ng/ml) also potentiated IL-1beta-mediated NO synthesis and inhibition of insulin release, whereas beta-nerve growth factor (NGF) (5 or 50 ng/ml) had no effect. mRNA for CNTF was expressed in rat islets and in islet cell lines. In conclusion, CNTF is constitutively expressed in pancreatic beta-cells and potentiates the beta-cell inhibitory effect of IL-1beta in association with increased iNOS expression and NO synthesis, an effect shared by IL-6 but not by beta-NGF. These findings indicate that signaling via gp130 influences islet NO synthesis associated with iNOS expression. We hypothesize that CNTF released from destroyed beta-cells during the inflammatory islet lesion leading to IDDM may potentiate IL-1beta action on the beta-cells.

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

“…We found that alloxan disrupts, whereas CNTF impairs, GSIS, in accordance with the literature and with results from our group [13,14,26]. The novelty here is that CNTF partially recovers GSIS in pancreatic islets from alloxan-treated mice.…”

Ciliary neurotrophic factor promotes survival of neonatal rat islets via the BCL-2 anti-apoptotic pathway

“…It has been suggested that CNTF, released from destroyed b-cells during the inflammatory process that occurs during the onset of type 1 diabetes, may act as a proinflammatory cytokine by potentiating the action of IL-1b on b-cells (Wadt et al 1998). However, to date, CNTF, in contrast to IL-6 (Ahima 2006) has not yet been tested as a differentiation and/ or survival factor in pancreatic islets.…”

“…Furthermore, CNTF expression has already been identified in b-cells (Wadt et al 1998). For these reasons, we decided to study the possible effects of CNTF on rat pancreatic islets differentiation and/or survival.…”

“…CNTF impairs glucose-stimulated insulin secretion (GSIS) and potentiates the inhibitory effect of IL-1b on GSIS, in cultured islets (Wadt et al 1998). In addition, it also exhibits many in vivo systemic effects, such as reduction of adiposity, body weight, hyperinsulinemia, and hyperglycemia in rats (Gloaguen et al 1997, Lambert et al 2001, Sakuma et al 2002, Sleeman et al 2003, Kelly et al 2004, Ott et al 2004, Ahima 2006, Graewin et al 2006.…”

Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells

“…Expression levels of Gadd45a, Gadd45b and Gadd45g were calculated by the standard curve method and the quantity of each cDNA was normalised for transcription factor Sp-1, showing no regulation by IL-1β [25]. The primers were as follows: Gadd45a, 5′-TGAGCTGCTGC TACTGGAGA-3′ and 5′-TGTGAT GAATGTGGGTTCGT -3′; Gadd45b, 5′-ATTGACATCG TCCGGGTATC-3′ and 5′-TGACAGTTCGTGACCAGG AG-3′; Gadd45g, 5′-GC ATCCTCATTTCGAATCCT-3′ and 5'-CACCCAGTCGTT GAAGCTG-3′; Sp-1, 5′-GG CTACCCCTACCTCAAAGG -3′ and 5′-CA CAACAT ACTGCCCACCAG-3′.…”