Interferon gamma

IFNG
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIFNG, IFG, IFI, interferon, gamma, interferon gamma, IMD69
External IDsOMIM: 147570 MGI: 107656 HomoloGene: 55526 GeneCards: IFNG
Orthologs
SpeciesHumanMouse
Entrez

3458

15978

Ensembl

ENSG00000111537

ENSMUSG00000055170

UniProt

P01579

P01580

RefSeq (mRNA)

NM_000619

NM_008337

RefSeq (protein)

NP_000610

NP_032363

Location (UCSC)Chr 12: 68.15 – 68.16 MbChr 10: 118.44 – 118.45 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Interferon gamma
Crystal structure of a biologically active single chain mutant of human interferon gamma
Identifiers
SymbolIFN gamma
PfamPF00714
Pfam clanCL0053
InterProIPR002069
SCOP21rfb / SCOPe / SUPFAM
Interferon gamma
Clinical data
Trade namesActimmune
AHFS/Drugs.comMonograph
MedlinePlusa601152
ATC code
Identifiers
IUPAC name
  • Human interferon gamma-1b
CAS Number
DrugBank
ChemSpider
  • none
UNII
ChEMBL
Chemical and physical data
FormulaC761H1206N214O225S6
Molar mass17145.65 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons.[5] The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes.[6] It was also shown to be produced in human lymphocytes.[7] or tuberculin-sensitized mouse peritoneal lymphocytes[8] challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed interferon gamma release assay used to test for tuberculosis. In humans, the IFNγ protein is encoded by the IFNG gene.[9][10]

Function

IFNγ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral, some bacterial and protozoan infections. IFNγ is an important activator of macrophages and inducer of major histocompatibility complex class II molecule expression. Aberrant IFNγ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFNγ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFNγ is produced predominantly by natural killer cells (NK) and natural killer T cells (NKT) as part of the innate immune response, and by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops[11][12] as part of the adaptive immune response. IFNγ is also produced by non-cytotoxic innate lymphoid cells (ILC), a family of immune cells first discovered in the early 2010s.[13]

Structure

The IFNγ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region.[14][15] This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6.

Figure 1. Line and cartoon representation of an IFNγ monomer.[15]

The biologically active dimer is formed by anti-parallel inter-locking of the two monomers as shown below. In the cartoon model, one monomer is shown in red, the other in blue.

Figure 2. Line and cartoon representation of an IFNγ dimer.[15]

Receptor binding

Figure 3. IFN dimer interacting with two IFNGR1 receptor molecules.[15]

Cellular responses to IFNγ are activated through its interaction with a heterodimeric receptor consisting of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR2). IFNγ binding to the receptor activates the JAK-STAT pathway. IFNγ also binds to the glycosaminoglycan heparan sulfate (HS) at the cell surface. However, in contrast to many other heparan sulfate binding proteins, where binding promotes biological activity, the binding of IFNγ to HS inhibits its biological activity.[16]

The structural models shown in figures 1-3 for IFNγ[15] are all shortened at their C-termini by 17 amino acids. Full length IFNγ is 143 amino acids long, the models are 126 amino acids long. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids.[17] Within this sequence of 17 amino acids lie two clusters of basic amino acids termed D1 and D2, respectively. Heparan sulfate interacts with both of these clusters.[18] In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFNγ-receptor complexes form.[16] Interactions between the D1 cluster of amino acids and the receptor may be the first step in complex formation. By binding to D1 HS may compete with the receptor and prevent active receptor complexes from forming.

The biological significance of heparan sulfates interaction with IFNγ is unclear; however, binding of the D1 cluster to HS may protect it from proteolytic cleavage.[18]

Biological activity

IFNγ is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells), macrophages, mucosal epithelial cells and NK cells. IFNγ is the only Type II interferon and it is serologically distinct from Type I interferons; it is acid-labile, while the type I variants are acid-stable.

IFNγ has antiviral, immunoregulatory, and anti-tumor properties.[19] It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:

  • Promotes NK cell activity
  • Increases antigen presentation and lysosome activity of macrophages.
  • Activates inducible nitric oxide synthase (iNOS)
  • Induces the production of IgG2a and IgG3 from activated plasma B cells
  • Causes normal cells to increase expression of class I MHC molecules as well as class II MHC on antigen-presenting cells—to be specific, through induction of antigen processing genes, including subunits of the immunoproteasome (MECL1, LMP2, LMP7), as well as TAP and ERAAP in addition possibly to the direct upregulation of MHC heavy chains and B2-microglobulin itself
  • Promotes adhesion and binding required for leukocyte migration
  • Induces the expression of intrinsic defense factors—for example, with respect to retroviruses, relevant genes include TRIM5alpha, APOBEC, and Tetherin, representing directly antiviral effects
  • Primes alveolar macrophages against secondary bacterial infections.[20][21]

IFNγ is the primary cytokine that defines Th1 cells: Th1 cells secrete IFNγ, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells ,[22] representing a positive feedback loop—while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for Th2 cells and IL-17 for Th17 cells.)

NK cells and CD8+ cytotoxic T cells also produce IFNγ. IFNγ suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK-RANKL signaling pathway, which otherwise stimulates the production of NF-κB.

Activity in granuloma formation

A granuloma is the body's way of dealing with a substance it cannot remove or sterilize. Infectious causes of granulomas (infections are typically the most common cause of granulomas) include tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and toxoplasmosis. Examples of non-infectious granulomatous diseases are sarcoidosis, Crohn's disease, berylliosis, giant-cell arteritis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, pulmonary rheumatoid nodules, and aspiration of food and other particulate material into the lung. The infectious pathophysiology of granulomas is discussed primarily here.

The key association between IFNγ and granulomas is that IFNγ activates macrophages so that they become more powerful in killing intracellular organisms. Activation of macrophages by IFNγ from Th1 helper cells in mycobacterial infections allows the macrophages to overcome the inhibition of phagolysosome maturation caused by mycobacteria (to stay alive inside macrophages). The first steps in IFNγ-induced granuloma formation are activation of Th1 helper cells by macrophages releasing IL-1 and IL-12 in the presence of intracellular pathogens, and presentation of antigens from those pathogens. Next the Th1 helper cells aggregate around the macrophages and release IFNγ, which activates the macrophages. Further activation of macrophages causes a cycle of further killing of intracellular bacteria, and further presentation of antigens to Th1 helper cells with further release of IFNγ. Finally, macrophages surround the Th1 helper cells and become fibroblast-like cells walling off the infection.

Activity during pregnancy

Uterine Natural Killer cells (NK) secrete high levels of chemoattractants, such as IFNγ in mice. IFNγ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site. This remodeling aids in the development of the placenta as it invades the uterus in its quest for nutrients. IFNγ knockout mice fail to initiate normal pregnancy-induced modification of decidual arteries. These models display abnormally low amounts of cells or necrosis of decidua.[23]

Production

Recombinant human interferon gamma, as an expensive biopharmaceutical, has been expressed in different expression systems including prokaryotic, protozoan, fungal (yeasts), plant, insect and mammalian cells. Human interferon gamma is commonly expressed in Escherichia coli, marketed as ACTIMMUNE®, however, the resulting product of the prokaryotic expression system is not glycosylated with a short half-life in the bloodstream after injection; the purification process from bacterial expression system is also very costly. Other expression systems like Pichia pastoris did not show satisfactory results in terms of yields.[24][25]

Therapeutic use

Interferon-γ 1b is approved by the U.S. Food and Drug Administration to treat chronic granulomatous disease[26] and osteopetrosis.[27]

It was not approved to treat idiopathic pulmonary fibrosis (IPF). In 2002, the manufacturer InterMune issued a press release saying that phase III data demonstrated survival benefit in IPF and reduced mortality by 70% in patients with mild to moderate disease. The U.S. Department of Justice charged that the release contained false and misleading statements. InterMune's chief executive, Scott Harkonen, was accused of manipulating the trial data, was convicted in 2009 of wire fraud, and was sentenced to fines and community service. Harkonen appealed his conviction to the U.S. Court of Appeals for the Ninth Circuit, and lost.[28] Harkonen was granted a full pardon on January 20, 2021.[29]

It is being studied at the Children’s Hospital of Philadelphia for the treatment of Friedreich's ataxia.[30]

Although not officially approved, Interferon-γ has also been shown to be effective in treating patients with moderate to severe atopic dermatitis.[31][32][33]

Potential use in immunotherapy

Interferon gamma is not approved yet for the treatment in any cancer immunotherapy. However, improved survival was observed when Interferon gamma was administrated to patients with bladder carcinoma and melanoma cancers. The most promising result was achieved in patients with stage 2 and 3 of ovarian carcinoma. On the contrary, it was stressed: "Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth."[34] The in vitro study of IFN-gamma in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-gamma leading to the growth inhibition or cell death, generally induced by apoptosis but sometimes by autophagy.[24] In addition, it has been reported that mammalian glycosylation of recombinant human interferon gamma, expressed in HEK293, improves its therapeutic efficacy compared to the unglycosylated form that is expressed in E. coli.[35]

Interactions

Interferon-γ has been shown to interact with Interferon gamma receptor 1.[36][37]

Diseases

Interferon-γ has been shown to be a crucial player in the immune response against some intracellular pathogens, including that of Chagas disease.[38] It has also been identified as having a role in seborrheic dermatitis.[39]

Regulation

There is evidence that interferon-gamma expression is regulated by a pseudoknotted element in its 5' UTR.[40] There is also evidence that interferon-gamma is regulated either directly or indirectly by the microRNAs: miR-29.[41] Furthermore, there is evidence that interferon-gamma expression is regulated via GAPDH in T-cells. This interaction takes place in the 3'UTR, where binding of GAPDH prevents the translation of the mRNA sequence.[42]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000111537 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000055170 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Gray PW, Goeddel DV (August 1982). "Structure of the human immune interferon gene". Nature. 298 (5877): 859–63. Bibcode:1982Natur.298..859G. doi:10.1038/298859a0. PMID 6180322. S2CID 4275528.
  6. ↑ Wheelock EF (July 1965). "Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin". Science. 149 (3681): 310–1. Bibcode:1965Sci...149..310W. doi:10.1126/science.149.3681.310. PMID 17838106. S2CID 1366348.
  7. ↑ Green JA, Cooperband SR, Kibrick S (June 1969). "Immune specific induction of interferon production in cultures of human blood lymphocytes". Science. 164 (3886): 1415–7. Bibcode:1969Sci...164.1415G. doi:10.1126/science.164.3886.1415. PMID 5783715. S2CID 32651832.
  8. ↑ Milstone LM, Waksman BH (November 1970). "Release of virus inhibitor from tuberculin-sensitized peritoneal cells stimulated by antigen". Journal of Immunology. 105 (5): 1068–71. PMID 4321289.
  9. ↑ Naylor SL, Sakaguchi AY, Shows TB, Law ML, Goeddel DV, Gray PW (March 1983). "Human immune interferon gene is located on chromosome 12". The Journal of Experimental Medicine. 157 (3): 1020–7. doi:10.1084/jem.157.3.1020. PMC 2186972. PMID 6403645.
  10. ↑ "Entrez Gene: IFNGR2".
  11. ↑ "Entrez Gene: INFG".
  12. ↑ Schoenborn JR, Wilson CB (2007). "Regulation of Interferon‐γ During Innate and Adaptive Immune Responses". Regulation of interferon-gamma during innate and adaptive immune responses. Advances in Immunology. Vol. 96. pp. 41–101. doi:10.1016/S0065-2776(07)96002-2. ISBN 978-0-12-373709-0. PMID 17981204.
  13. ↑ Artis D, Spits H (January 2015). "The biology of innate lymphoid cells". Nature. 517 (7534): 293–301. Bibcode:2015Natur.517..293A. doi:10.1038/nature14189. PMID 25592534. S2CID 4386692.
  14. ↑ Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, Trotta PP, Bugg CE (May 1991). "Three-dimensional structure of recombinant human interferon-gamma". Science. 252 (5006): 698–702. Bibcode:1991Sci...252..698E. doi:10.1126/science.1902591. PMID 1902591.
  15. 1 2 3 4 5 PDB: 1FG9​; Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, et al. (September 2000). "Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex". Structure. 8 (9): 927–36. doi:10.1016/S0969-2126(00)00184-2. PMID 10986460.
  16. 1 2 Sadir R, Forest E, Lortat-Jacob H (May 1998). "The heparan sulfate binding sequence of interferon-gamma increased the on rate of the interferon-gamma-interferon-gamma receptor complex formation". The Journal of Biological Chemistry. 273 (18): 10919–25. doi:10.1074/jbc.273.18.10919. PMID 9556569.
  17. ↑ Vanhaverbeke C, Simorre JP, Sadir R, Gans P, Lortat-Jacob H (November 2004). "NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides". The Biochemical Journal. 384 (Pt 1): 93–9. doi:10.1042/BJ20040757. PMC 1134092. PMID 15270718.
  18. 1 2 Lortat-Jacob H, Grimaud JA (March 1991). "Interferon-gamma binds to heparan sulfate by a cluster of amino acids located in the C-terminal part of the molecule". FEBS Letters. 280 (1): 152–4. doi:10.1016/0014-5793(91)80225-R. PMID 1901275. S2CID 45942972.
  19. ↑ Schroder K, Hertzog PJ, Ravasi T, Hume DA (February 2004). "Interferon-gamma: an overview of signals, mechanisms and functions". Journal of Leukocyte Biology. 75 (2): 163–89. doi:10.1189/jlb.0603252. PMID 14525967. S2CID 15862242.
  20. ↑ Hoyer FF, Naxerova K, Schloss MJ, Hulsmans M, Nair AV, Dutta P, et al. (November 2019). "Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge". Immunity. 51 (5): 899–914.e7. doi:10.1016/j.immuni.2019.10.010. PMC 6892583. PMID 31732166.
  21. ↑ Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M, Damjanovic D, et al. (November 2018). "Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity". Cell. 175 (6): 1634–1650.e17. doi:10.1016/j.cell.2018.09.042. PMID 30433869.
  22. ↑ Luckheeram, Rishi Vishal; Zhou, Rui; Verma, Asha Devi; Xia, Bing (2012). "CD4+T Cells: Differentiation and Functions". Journal of Immunology Research. 2012: 925135. doi:10.1155/2012/925135. PMC 3312336. PMID 22474485.
  23. ↑ Ashkar AA, Di Santo JP, Croy BA (July 2000). "Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy". The Journal of Experimental Medicine. 192 (2): 259–70. doi:10.1084/jem.192.2.259. PMC 2193246. PMID 10899912.
  24. 1 2 Razaghi A, Owens L, Heimann K (December 2016). "Review of the recombinant human interferon gamma as an immunotherapeutic: Impacts of production platforms and glycosylation". Journal of Biotechnology. 240: 48–60. doi:10.1016/j.jbiotec.2016.10.022. PMID 27794496.
  25. ↑ Razaghi A, Tan E, Lua LH, Owens L, Karthikeyan OP, Heimann K (January 2017). "Is Pichia pastoris a realistic platform for industrial production of recombinant human interferon gamma?". Biologicals. 45: 52–60. doi:10.1016/j.biologicals.2016.09.015. PMID 27810255.
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  27. ↑ Key LL, Ries WL, Rodriguiz RM, Hatcher HC (July 1992). "Recombinant human interferon gamma therapy for osteopetrosis". The Journal of Pediatrics. 121 (1): 119–24. doi:10.1016/s0022-3476(05)82557-0. PMID 1320672.
  28. ↑ Silverman E (September 2013). "Drug Marketing. The line between scientific uncertainty and promotion of snake oil". BMJ. 347: f5687. doi:10.1136/bmj.f5687. PMID 24055923. S2CID 27716008.
  29. ↑ "Statement from the Press Secretary Regarding Executive Grants of Clemency". whitehouse.gov. January 20, 2021 – via National Archives.
  30. ↑ Seyer L, Greeley N, Foerster D, Strawser C, Gelbard S, Dong Y, et al. (July 2015). "Open-label pilot study of interferon gamma-1b in Friedreich ataxia". Acta Neurologica Scandinavica. 132 (1): 7–15. doi:10.1111/ane.12337. PMID 25335475. S2CID 207014054.
  31. ↑ Akhavan A, Rudikoff D (June 2008). "Atopic dermatitis: systemic immunosuppressive therapy". Seminars in Cutaneous Medicine and Surgery. 27 (2): 151–5. doi:10.1016/j.sder.2008.04.004. PMID 18620137.
  32. ↑ Schneider LC, Baz Z, Zarcone C, Zurakowski D (March 1998). "Long-term therapy with recombinant interferon-gamma (rIFN-gamma) for atopic dermatitis". Annals of Allergy, Asthma & Immunology. 80 (3): 263–8. doi:10.1016/S1081-1206(10)62968-7. PMID 9532976.
  33. ↑ Hanifin JM, Schneider LC, Leung DY, Ellis CN, Jaffe HS, Izu AE, et al. (February 1993). "Recombinant interferon gamma therapy for atopic dermatitis". Journal of the American Academy of Dermatology. 28 (2 Pt 1): 189–97. doi:10.1016/0190-9622(93)70026-p. PMID 8432915.
  34. ↑ Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, et al. (April 2015). "IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer". British Journal of Cancer. 112 (9): 1501–9. doi:10.1038/bjc.2015.101. PMC 4453666. PMID 25867264.
  35. ↑ Razaghi A, Villacrés C, Jung V, Mashkour N, Butler M, Owens L, Heimann K (October 2017). "Improved therapeutic efficacy of mammalian expressed-recombinant interferon gamma against ovarian cancer cells". Experimental Cell Research. 359 (1): 20–29. doi:10.1016/j.yexcr.2017.08.014. PMID 28803068. S2CID 12800448.
  36. ↑ Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, et al. (September 2000). "Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex". Structure. 8 (9): 927–36. doi:10.1016/S0969-2126(00)00184-2. PMID 10986460.
  37. ↑ Kotenko SV, Izotova LS, Pollack BP, Mariano TM, Donnelly RJ, Muthukumaran G, et al. (September 1995). "Interaction between the components of the interferon gamma receptor complex". The Journal of Biological Chemistry. 270 (36): 20915–21. doi:10.1074/jbc.270.36.20915. PMID 7673114.
  38. ↑ Leon Rodriguez DA, Carmona FD, Echeverría LE, González CI, Martin J (March 2016). "IL18 Gene Variants Influence the Susceptibility to Chagas Disease". PLOS Neglected Tropical Diseases. 10 (3): e0004583. doi:10.1371/journal.pntd.0004583. PMC 4814063. PMID 27027876.
  39. ↑ Trznadel-Grodzka E, Błaszkowski M, Rotsztejn H (November 2012). "Investigations of seborrheic dermatitis. Part I. The role of selected cytokines in the pathogenesis of seborrheic dermatitis". Postepy Higieny I Medycyny Doswiadczalnej. 66: 843–7. doi:10.5604/17322693.1019642. PMID 23175340.
  40. ↑ Ben-Asouli Y, Banai Y, Pel-Or Y, Shir A, Kaempfer R (January 2002). "Human interferon-gamma mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR". Cell. 108 (2): 221–32. doi:10.1016/S0092-8674(02)00616-5. PMID 11832212. S2CID 14722737.
  41. ↑ Asirvatham AJ, Gregorie CJ, Hu Z, Magner WJ, Tomasi TB (April 2008). "MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components". Molecular Immunology. 45 (7): 1995–2006. doi:10.1016/j.molimm.2007.10.035. PMC 2678893. PMID 18061676.
  42. ↑ Chang CH, Curtis JD, Maggi LB, Faubert B, Villarino AV, O'Sullivan D, et al. (June 2013). "Posttranscriptional control of T cell effector function by aerobic glycolysis". Cell. 153 (6): 1239–51. doi:10.1016/j.cell.2013.05.016. PMC 3804311. PMID 23746840.

Further reading

  • Hall SK (1997). A commotion in the blood: life, death, and the immune system. New York: Henry Holt. ISBN 978-0-8050-5841-3.
  • Ikeda H, Old LJ, Schreiber RD (April 2002). "The roles of IFN gamma in protection against tumor development and cancer immunoediting". Cytokine & Growth Factor Reviews. 13 (2): 95–109. doi:10.1016/S1359-6101(01)00038-7. PMID 11900986.
  • Chesler DA, Reiss CS (December 2002). "The role of IFN-gamma in immune responses to viral infections of the central nervous system". Cytokine & Growth Factor Reviews. 13 (6): 441–54. doi:10.1016/S1359-6101(02)00044-8. PMID 12401479.
  • Dessein A, Kouriba B, Eboumbou C, Dessein H, Argiro L, Marquet S, et al. (October 2004). "Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis". Immunological Reviews. 201: 180–90. doi:10.1111/j.0105-2896.2004.00195.x. PMID 15361241. S2CID 25378236.
  • Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
  • Copeland KF (December 2005). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini Reviews in Medicinal Chemistry. 5 (12): 1093–101. doi:10.2174/138955705774933383. PMID 16375755.
  • Chiba H, Kojima T, Osanai M, Sawada N (January 2006). "The significance of interferon-gamma-triggered internalization of tight-junction proteins in inflammatory bowel disease". Science's STKE. 2006 (316): pe1. doi:10.1126/stke.3162006pe1. PMID 16391178. S2CID 85320208.
  • Tellides G, Pober JS (March 2007). "Interferon-gamma axis in graft arteriosclerosis". Circulation Research. 100 (5): 622–32. CiteSeerX 10.1.1.495.2743. doi:10.1161/01.RES.0000258861.72279.29. PMID 17363708. S2CID 254247.
  • Overview of all the structural information available in the PDB for UniProt: P01579 (Interferon gamma) at the PDBe-KB.

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